DRUG DISPOSITION
Clin. Pharmacokinet. 1996 Oct; 31 (4): 257-274
0312-5963/96/00 10-0257/$00.00/0
© Adis International Limited. AU rights reserved .
Clinical Pharmacokinetics and Metabolism of Chloroquine Focus on Recent Advancements Julie Ducharme and Robert Farinotti Faculte de Pharmacie, Universite de Paris XI, Chatenay-Malabry, France
Contents Summary . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . 1. Clinical Pharmacokinetics in Healthy Individuals or Otherwise Healthy Arthritic Patients .. . .. . 1.1 Absorption and Bioavailability 1.2 Distribution. 1.3 Elimination . . . . . . . . . . . . 2. Metabolism . . . . . . . . . . . . . . 2.1 Metabolite Blood Concentrations 2.2 Microsomal Metabolism . . . .. 2.3 Non-Microsomal Metabolism .. 3. Clinical Pharmacokinetics in Malaria 3.1 Absorption and Distribution . . . 3.2 Elimination . . . . . . . . . . . .. 4. Clinical Pharmacokinetics in Malnutrition . 4.1 Absorption and Distribution . . . . . . 4.2 Elimination . . . . . . . . . . . . . . . . 5. Clinical Pharmacokinetics in Different Ethnic Groups 5.1 Absorption and Distribution . . . . . . . . . . . . 5.2 Elimination . .. . . . . .. .. .. ... .. .. . . 6. Clinical Pharmacokinetics in Pregnancy and Lactation 7. Pharmacokinetic-Pharmacodynamic Relationships 7. 1 Parent Drug . . . . . . . . 7.2 Chloroquine Metabolites . . . . . .. . .. .. . 7.3 Chloroquine Resistance . . . . . . . . . . . . . . 8. Stereoselective Pharmacokinetics and Pharmacodynamics 8.1 Pharmacodynamic Potency 8.2 In Vitro Protein Binding . . . . . . . . 8.3 In Vivo Body Disposition . . . . . . . 8.4 Clinical Consequences of Chirality. 9. Conclusion . . . . . . . . . . . . . . . . .
Summary
257 259 259 259 260 260 261 262 263 264 264 264 264 265 265 265 265 266 266 267 267 267 267 268 268 268 269 269 270
This paper presents the current state of knowledge on chloroquine disposition, with special emphasis on stereoselectivity and microsomal metabolism. In addition, the impact of the patient's physiopathological status and ethnic origin on chloroquine pharmacokinetics is discussed.
258
Ducharme & Farinotti
In humans, chloroquine concentrations decline multiexponentially. The drug is extensively distributed, with a volume of distribution of 200 to 800 L/kg when calculated from plasma concentrations and 200 L/kg when estimated from whole blood data (concentrations being 5 to 10 times higher). Chloroquine is 60% bound to plasma proteins and equally cleared by the kidney and liver. Following administration chloroquine is rapidly dealkylated via cytochrome P450 enzymes (CYP) into the pharmacologically active desethylchloroquine and bisdesethylchloroquine. Desethylchloroquine and bisdesethylchloroquine concentrations reach 40 and 10% of chloroquine concentrations, respectively; both chloroquine and desethylchloroquine concentrations decline slowly, with elimination half-lives of 20 to 60 days. Both parent drug and metabolite can be detected in urine months after a single dose. In vitro and in vivo, chloroquine and desethylchloroquine competitively inhibit CYP2D 1I6-mediated reactions. Limited in vitro studies and preliminary data from clinical experiments and observations point to CYP3A and CYP2D6 as the 2 major isoforms affected by or involved in chloroquine metabolism. In vitro efficacy studies did not detect any difference in potency between chloroquine enantiomers but, in vivo in rats, S(+)-chloroquine had a lower dose that elicited 50% of the maximal effect (ED950) than that of R(-)-chloroquine. Stereoselectivity in chloroquine body disposition could be responsible for this discrepancy. Chloroquine binding to plasma proteins is stereoselective, favouring S(+)-chloroquine (67% vs 35% for the R-enantiomer). Hence, unbound plasma concentrations are higher for R(-)-chloroquine. Following separate administration of the individual enantiomers, R(-)-chloroquine reached higher and more sustained blood concentrations. The shorter half-life of S( +)-chloroquine appears secondary to its faster clearance. Blood concentrations of the S( + )-forms of desethylchloroquine always exceeded those of the R(-)-forms, pointing to a preferential metabolism of S( +)-chloroquine. In spite of the increasing prevalence of resistant strains of malaria, 4 decades after its introduction chloroquine is still one of the most widely used antimalarial drugs, alone or in combination with other agents.[l-3] Chloroquine is inexpensive, easily available, relatively well-tolerated, and curative after only a few doses. These are essential features for its clinical use in developing countries with limited. resourcesJI] Although the appearance of chloroquine-resistant Plasmodium Jalciparum is a serious clinical problem,[3] any documentation of resistance in previously-sensitive strains requires the careful exclusion of confounding factors, such as noncompliance, inadequate drug administration, and dosage, and more importantly, the influence of drug-drug or drug-disease interactions. Hence, the develop© Adis International Limited. All rights reserved.
ment of sensitive and specific analytical methods and the careful planning of pharmacokinetic studies are key to the adequate recognition of these important factors, and to the safe and effective use of existing antimalarial agents. In view of the expanding indications of antimalarial agents to the long term treatment of rheumatoid arthritis and systemic lupus erythematosus,[4] the clinical pharmacokinetics of chloroquine need to be reassessed. This paper presents the current state of knowledge on chloroquine disposition, with special emphasis on the more recent investigations of stereoselectivity and microsomal metabolism. In addition, the impact of the patient's physiopathological status and medication profile on the drug pharmacokinetics are discussed. Clin. Phormacoklnet. 1996 Oct; 31 (4)
259
Clinical Pharmacokinetics and Metabolism of Chloroquine
1. Clinical Pharmacokinetics in Healthy Individuals or Otherwise Healthy Patients with Arthritis Newer analytical methods combining greater specificity and sensitivity led to a better understanding of chloroquine pharmacokinetics. Earlier studies postulated that chloroquine pharmacokinetics were nonlinear and dose-dependent,[5.8] conclusions that were challenged on the basis of methodological shortcomingsP-ll] Assay limitations of earlier kinetic studies (inability to differentiate parent from metabolites or monodesethylated from bisdesethylated metabolites and insufficient sensitivity),[12,13] coupled with the physicochemical characteristics of the chloroquine molecule (adsorption to glass, binding to blood cell components),[14-17] and insufficient durations of sampling,[7,15,18] led to a significant underestimation of the later distribution and elimination phases of the drug. The reader is referred to the recent review by Krishna and White[19] for detailed tables of chloroquine pharmacokinetic parameters. 1.1 Absorption and Bioavailability
Following a single oral dose, chloroquine bioavailability was found to be nearly complete at 78 to 89 ± 16%.[20] This was confirmed by similar urinary recoveries of unchanged chloroquine following enteral and parenteral administrations (47 ± 5% of the dose taken intravenously vs 42 to 46 ± 8% orally))20] Although the mean values approached 100% bioavailability, interpatient variability was very highP,IO·20] The bioavailability of the oral solution ranged from 52 to 102%, while that of the tablet varied between 67 and 114%.[19] Hence, chloroquine bioavailability might not be as complete as was previously thought.[l8] 1.2 Distribution 1.2. 1 Blood and Tissue Concentrations
Whole blood, plasma, or serum concentrations decline multiexponentially as the drug is distributed to produce an apparent volume of distribution (V d) several orders of magnitude larger than that © Adis International Limited. All rights reserved.
of the central compartment (200 L/kg when calculated from whole blood concentrations to 200 to 800 L/kg from plasma data).[8,20-22] This extensive Vd illustrates the ability of the drug to bind to various body tissues, particularly to the cellular components of blood. Following oral administration, whole blood concentrations are 5 to 10 times higher than those observed in plasma,[8.15] with high proportions of the drug and its main metabolite bound to platelets and granulocytes)15,16.23] Chloroquine concentration vs time course in whole blood was parallel to that in plasma,[8] illustrating distribution differences and excluding any metabolism within the blood cells. Serum concentrations are higher than plasma concentrations because of the release of plateletbound chloroquine during clotting) 11,16.23] Centrifugation conditions need to be carefully established and standardised (e.g. 2000g for 15 minutes),[Il] since a centrifugal force lower than 500g for less than 15 minutes may lead to falsely high plasma concentrations by platelet disruption. Methodological problems can be avoided by using whole blood concentrations for pharmacokinetic estimations.l 23 ] Distribution studies in monkeys and albino rats showed that chloroquine is extensively sequestered in tissues, with the liver, spleen, kidney and lungs being the main repositories.[24,25] In humans, concentrations averaging 10-6 moUL (or 320 Ilg/L) were measured in muscle and brain tissue, while higher concentrations of approximately 10-4 mollL were measured in the marrow, liver, spleen, and leucocytes)15,26] In fatal overdose cases, the highest chloroquine concentrations were found in the liver.l 27 ] Extremely high concentrations of chloroquine (10- 3 mollL) can be found in melanincontaining tissues such as the choroid, and the ciliary body of the eye)26,28] 1.2.2 Lysosomal Trapping
Chloroquine is a basic amine with a 4-aminoquinoline nucleus at one end of the planar molecule and a lipophilic side chain at the other end (fig. 1).[29] At physiological pH, a significant concentration of the lipophilic free base is in equilibrium with its protonated form.[30] The drug passively Clin. Pharmacokinet. 1996 Oct: 31 (4)
260
Ducharme & Farinotti
diffuses into the cell in a lipophilic unprotonated state, but once it enters the acidic environment of the lysosome (pH of approximately 5),[31) it becomes protonated and the drug is trapped within the vesicleP6,32) Entry into the cell is by passive diffusion,[33) whereas the trapping mechanism involves a proton pump, which requires energy. Thereore, the extensive tissue distribution of chloroquine is likely to result from its amphiphilic nature, combining the lipophilicity of the free base form and the proton-accepting properties of the weak base,l34) It is uncertain whether the weak base effect plays a role in the rheumatological and antimalarial effectiveness of chloroquine.[26,31,35,36) Platelets and leucocytes are able to concentrate chloroquine by ion trapping within the acidic lysosomes.(26) While red blood cells do not contain these organelles, malaria-infected erythrocytes can accumulate chloroquine inside the acidic digestive food vacuole(s) of the parasite, according to the pH gradient.[37) 1.2.3 Protein Binding
In vitro, in plasma from healthy volunteers, ultrafiltration or equilibrium dialysis techniques reveal that 58 to 61 % of chloroquine is bound to plasma proteins.[38-41) In plasma from patients with rheumatoid arthritis, the extent of binding was similar at 64%.141 ) In purified protein solutions, about 39% of chloroquine was bound to albumin compared with 42 to 48% in aI-acid glycoprotein.[38-40] In a mixture of these proteins, chloroquine binding was not as high as in plasma,[4l) suggesting additional binding sites, probably on lipoproteins. Since chloroquine binding to plasma proteins is moderate and its Vd extensive, chloroquine disposition is un~ likely to be affected by minor differences in protein binding. 1.3 Elimination
In healthy volunteers, after a single oral dose of 300mg, chloroquine concentrations could be detected in blood and urine up to 52 and 119 days postdose, respectively,l20) Similarly, after a lO-week malaria prophylaxis regimen 300 mg/week, chloro© Adis International Limited. All rights reserved.
quine was still present in serum after 70 days,(42) and in urine up to 1 year after the last dose.[42,43) Distribution and redistribution processes (from the various body compartments back to the intravascular space) rather than slow drug elimination, are the predominant factors governing chloroquine blood concentrations for months following its single dose administration,l20,44) Indeed, despite its long halflife, ranging from 20 to 60 days, chloroquine has a relatively high total clearance, approximating 0.10 Lih/kg from whole blood data and 0.7 to 1 L/h/kg from plasma data.l 8,20,21,42) In patients treated for long term arthritis,[45,46) or following multiple weekly doses for malaria prophylaxis,[22) the total plasma clearance of chloroquine was estimated at 0.35 to 1 Lih/kg. In urine, following single or multiple dose administration in healthy volunteers or otherwise healthy patients with arthritis, approximately 50% of the given dose was recovered as unchanged chloroquine, and 10% as desethylchloroquine, its primary metabolite.l 18 ,20,45-47) After a single oral dose, chloroquine renal clearance accounted for 50% of its total clearance,[20,48) and was much greater than the glomerular filtration rate, showing that a significant proportion of chloroquine is renally secreted,l20) Since both the liver and the kidney contribute to chloroquine elimination, the dosage may have to be modified in patients with renal or hepatic insufficiency. [4,49)
2. Metabolism Clinically there are marked interindividual variations in the pha~macokinetics of chloroquine, following single or multiple doses.! I8,20,22,42,48,50) To a great extent, these differences may reflect a diversity in metabolism. Approximately 30 to 50% of an administered dose of chloroquine is transformed by the liver.(43) Since metabolising enzymes exhibit a large degree of interindividual variability in their level of expression, the identification of the enzyme system(s) involved in the biotransformation of chloroquine may provide useful insights into the clinical use of chloroquine. Clin. Pharmacokinet. 1996 Oct; 31 (4)
261
Clinical Pharmacokinetics and Metabolism of Chloroquine
Chloroquine
Deselhyl-chloroquine
Bisdesethyl-chloroquine
7-Chloro-4-aminoquinoline
Fig. 1. Chemical structures of chloroquine and of three of its metabolites, desethylchloroquine, bisdesethylchloroquine and 7-chloro4-aminoquinoline.
2.1 Metabolite Blood Concentrations
Following administration, chloroquine is rapidly dealkylated into the pharmacologically active desethylchloroquine, bisdesethylchloroquine and 7-chloro-4-aminoquinoline (fig. 1))1,8,18,20,48] Other metabolites include chloroquine side chain N-oxide and chloroquine di-N-oxide, which are inconsistently detected in plasma samp1es;l48] because of their high polarity, they are thought to be readily excreted. Other uncharacterised molecules may also be present in low concentrations.l48 ] Following single oral doses of chloroquine to healthy volunteers, desethylchloroquine is rapidly detected in blood and plasma, reaching concentra-. tions of about 20 to 30% that of the parent drug)8,20] Desethylchloroquine concentrations decline slowly, with a terminal elimination half-life approximating 30 to 60 days.l8,20,21,42] Hence, following a 10 week-prophylactic treatment against malaria, desethylchloroquine was still detected in urine 1 year after the last dose)42] In patients receiving long term chloroquine treatment, desethylchloroquine accounted for 36 to 48% of chloroquine steady-state plasma or © Adis International Limited. All rights reserved.
whole blood concentrations. l38 ,45] Theoretically, some of these percentages might have been overestimated,l20,42] since the analytical method of Alvan et al)13] measured the combination of desethylchloroquine and bisdesethylchloroquine rather than only desethylchloroquine. However, since bisdesethylchloroquine is a less significant metabolite, different analytical methods l13 ,51,52] have yielded comparable desethylchloroquine concentrations. Whole blood concentrations of bisdesethylchloroquine approximated 2 to 5% and 5 to 13% of chloroquine concentrations after single l8 ] and multiple[38,45] oral doses, respectively. Following 3 weeks of once weekly, twice weekly, or once daily chloroquine, bisdesethylchloroquine plasma area under the concentration-time curve (AUC)o_~ remained 3-times lower than that of desethylchloroquine. l22 ] In a recent article on chloroquine single-dose pharmacokinetics in healthy volunteers, 7-chloro4-aminoquinolone was found to be the major circulating metabolite, with plasma concentrations twice as high as those of the parent drug.l48 ] Desethylchloroquine and bisdesethylchloroquine Clin. Pharmacokinet. 1996 Oct; 31 (4)
Ducharme & Farinotti
262
plasma profiles were higher than those previously reported following single oral doses, i.e. amounting to 46 and 30% of chloroquine plasma concentrations, respectively. However, the former are unlikely to reflect the metabolite: parent ratios expected following a single oral dose as all individuals had taken chloroquine in the past 2 to 12 months. Residual plasma concentrations of chloroquine and its derivatives were detected in all 'predose' plasma samples, but whether or not these residual concentrations were substracted from the measured concentrations was not mentioned. Furthermore, the investigators sampled blood and urine for only 6 days post-dose, therefore precluding the estimation of elimination half-lives. Nevertheless, their results suggest similar early disposition half-lives for chloroquine and its 3 dealkylated metabolites. In patients on long term chloroquine therapy for rheumatoid arthritis, 7-chloro-4aminoquinolone could not be detected in any blood samples.l 381 2.2 Microsomal Metabolism
Although chloroquine is thought to be N-dealkylated via the cytochrome P450 (CYP) enzyme system, rigorous experimental data substantiating such a supposition are still lacking. Only incomplete experiments in vitro and in vivo in animals, together with a few anecdotal reports based on in vivo drug-drug interactions in humans, allow some preliminary conclusions to be drawn. 2.2. 1 In Vitro Studies
Even if chloroquine plasma concentrations rarely exceed the micromolar range, liver concentrations may be several hundred times higher (10-4 mollL).[IS,26 1 In rats, liver to plasma ratios ranged· from 209 to 541.l S3 ) These concentrations dictate the use of micro molar to hundreds of micromolar concentrations for in vitro studies such as drug incubations in characterised human microsomes or in cultured hepatocytes. Higher concentrations could lead to biased results, which could overemphasis the role of lower affinity-higher capacity enzyme systems at the expense of the more clinically relevant higher affinity-lower capacity enzyme sys© Adis International Limited, All rights reserved ,
terns. However, the finding that desethylchloroquine is already detectable in plasma in vivo during the absorption phase of the parent compound, suggests an enzymatic system with a high capacity. In vitro in rat microsomes, and in vivo in rats, chloroquine was found to competitively inhibit the CYP2Dl-mediated a-hydroxylation of metopro101.[54) In human livers, chloroquine still inhibited the CYP2D6-mediated metabolism of metoprolol but the extent of inhibition was about 2 orders of magnitude weaker than in rats and showed considerable interindividual variability.ls4) Subsequent studies, also in human liver microsomes, showed that chloroquine and desethylchloroquine inhibited another CYP2D6-mediated reaction, i.e. the 1'-hydroxylation of bufuralol, with a Ki value of 15 IlmollL;[SS) however, a more recent investigation did not confirm such a low Ki.f S6 ) In human liver microsomes from an extensive CYP2D6 metaboliser, Halliday et aJ.lS6) estimated mean concentration of drug that inhibited enzyme activity by 50% (ICso) values of 127 IlmollL for chloroquine compared with 0.043 IlmollL for quinidine and 30 IlmollL for quinine. Low Ki values would indicate a high affinity for the CYP2D6 binding site, chloroquine and desethylchloroquine being either substrates or nonsubstrate inhibitors of the enzyme. Chloroquine possesses basic nitrogen-substituents, which could possibly interact with the carboxylic groups of the CYP2D6 binding sites according to a predictive model for CYP2D6 substrates.ls7 ) On the other hand, chloroquine could resemble quinidine, which is a potent CYP2D6 inhibitor and CYP3A substrate.lS6.S81 In any case, this could have important clinical significance in view of the extremely long half-lives of chloroquine and its metabolites,[8,20.42) and the polymorphic distribution of CYP2D6,[S9.60) the distribution of which is extremely dependent upon the ethnic origin of the individuals. [61) 2.2.2 In Vivo Studies
The formation rates of desethylchloroquine and bisdesethylchloroquine were strongly correlated in vivo (r2 = 0.83),[48) suggesting that their formation Clin, Pharmacokinet, 1996 Oct; 31 (4)
Clinical Pharmacokinetics and Metabolism of Chloroquine
263
(from chloroquine and desethylchloroquine, respectively) might be mediated by the same enzyme system. This is consistent with previous results in characterised human microsomes showing similar Ki values for both compounds. ISS] In a small crossover study of 6 healthy volunteers, after concomitant administration of single doses of chloroquine 300mg and the CYP2D6 substrate and inhibitor imipramine 50mg,162,63] there was no difference in the plasma and urinary profiles of the parent drugs and their metabolites compared to single-agent administrations.l 64 ] Similarly, when healthy individuals were phenotyped for CYP2D6 (with debrisoquine) and for CYP2Cl9 (with S-mephenytoin), phenotyping ratios were not significantly different before or after single doses of chloroquine.l 6S ] Rather than excluding any interaction between CYP2D6 and chloroquine, this study could indicate that multiple in vivo doses of chloroquine (or imipramine) are necessary to achieve any CYP2D6 inhibition.[62] In addition, in vitro-in vivo discrepancies could be due to the extensive body distribution of chloroquine, reducing the concentrations of chloroquine available for binding with CYP2D6. Concomitant administration of a single dose of chloroquine 300mg and cimetidine 400mg daily starting 4 days prior to chloroquine, resulted in a 50% increase in chloroquine half-life, associated with a 50% decrease in its clearance.[66] Since the AUC of desethylchloroquine decreased by 47%, cimetidine probably decreased chloroquine clearance by inhibiting its hepatic desethylation. The imidazole ring of the cimetidine molecule is thought to bind to the prosthetic heme iron of CYP,[67] leading to alterations of CYP redox poten-' tial and to subsequent impairment of their reduction and binding of molecular oxygen.l68 ]Although cimetidine has been found to inhibit the hepatic metabolism of numerous xenobiotics, its inhibiting effects may be selective for specific isoforms. In vitro, in human liver micro somes and geneticallyengineered proteins produced by yeasts, cimetidine showed a high affinity for CYP3As and
CYP2D6, an intermediate affinity for CYPIA2 and CYP2EI and a low affinity for CYP2Cs.l69] In contrast, there was no difference in the single 'dose pharmacokinetics of chloroquine 300mg in ranitidine-treated patients (250mg daily starting 4 days prior to chloroquine).[70] Since ranitidine has less affinity for CYP binding sites and has not been specifically identified as an enzymatic inhibitor,[71] these results are consistent with the involvement of microsomal enzymes in chloroquine metabolism in vivo. The initiation of chloroquine treatment in a cyclosporin-treated patient resulted in a sudden increase in its cyclosporin serum concentrations with transient nephrotoxicity.l72,73] Since cyclosporin is a CYP3A substrate,[74] this could reflect competitive inhibition for metabolism. Thus, all reports point to CYP3As and CYP2D6 as the 2 major isoforms affected by or involved in the metabolism of chloroquine. Even though chloroquine is presumed to be mostly metabolised in the liver, extra-hepatic sites of microsomal metabolism could also be of clinical significance in view of the extensive tissue distribution of the drug and the extra-hepatic distribution of CYP3As,l7S]
© Adis International Limited. All rights reserved.
2.3 Non-Microsomal Metabolism
Nwankwo and associates[76] recently reported that chloroquine may alter N-acetyltransferase (NAT) activity in the rat. Pretreatment with single or multiple doses of chloroquine resulted in the reduced acetylation of isoniazid and sulfadimidine.[76] However, in the rat the urinary concentrations of sulphadimidine and its acetylated metabolite appearS!d to be too low to serve as an adequate model of acetylation.[77,78] Indeed, Svensson et aLi79] found only slight reductions in NAT activity when chloroquine was added in vitro. In addition, in vivo in rats, a 4-day chloroquine pretreatment did not alter NAT activity,l79] In human liver, brain, kidney and gut, chloroquine is a potent noncompetitive inhibitor of histamine N-methyltransferase,[80] the enzyme catalysing the main pathway of histamine metabolism. Among 100 livers, the rate of histamine methylaClin. Pharmacokinet. 1996 Oct; 31 (4)
Ducharme & Farinotti
264
tion was found to vary by approximately 30%)81] Since higher tissue concentrations of histamine could be associated with adverse effects, individuals with lower enzyme expression would be at a greater risk of histamine-induced toxicity. 3. Clinical Pharmacokinetics in Malaria The reader is referred to the review article by Krishna and White[19] for a tabulation of chloroquine pharmacokinetic parameters in patients with malaria. 3.1 Absorption and Distribution
In Nigerian children with acute uncomplicated malaria, chloroquine absorption appeared reliable as peak chloroquine concentrations were achieved within 0.5 hours, both in plasma and red cells)82,83] Compared to a historical control group formed from other studies,[20] the authors did not observe any difference between healthy individuals and patients with malaria. Compared to age- and race-matched individuals, Thai patients suffering from P. vivax malaria had significantly higher blood concentrations and AVCs of both chloroquine and desethy1chloroquine)84] Since chloroquine pharmacokinetics showed no difference between Thai individuals and patients with malaria following intravenous administration,[85] the authors concluded that malariainduced absorption changes contributed to the increased systemic exposure to chloroquine. Indeed, higher plasma and blood concentrations during the initial phase of treatment have been observed for other antimalarial agents,[86-88] Since acute malaria can induce elevations in
day treatment when parasitaemia was down to 0%, the same ratio fell to about 7)82] Hence, drug-sensitive parasites seem to concentrate quinoline derivatives,[87] differences in red cell concentrations being a reflection of varying degrees of parasitaemia and different stages of parasite development.[88] 3.2 Elimination
Following a single intravenous dose of chloroquine the elimination half-life and clearance there were significantly different between healthy individuals and patients with malaria)85,90] Although it has not been investigated with chloroquine, malaria can induce changes in drug elimination which could become significant following multiple drug therapy. In patients with malaria, plasma concentrations of quinine and quinidine were increased and their elimination half-lives prolonged, secondary to their decreased Vd (increased binding to
1996 Oct; 31 (4)
265
Clinical Pharmacokinetics and Metabolism of Chloroquine
4.1 Absorption and Distribution
Following a single oral dose of chloroquine 600mg, there was no difference in the plasma or whole blood concentrations between healthy and malnourished individuals up to 72 hours postdoseJ95] Since malnourished individuals received a higher chloroquine dose on a mg/kg of bodyweight basis, they appeared to be handling chloroquine more efficiently than healthy individuals. Similarly, after the oral administration of a single dose of 10 mg/kg to Nigerian children, peak plasma chloroquine concentrations were lower in children with Kwashiorkor than in healthy children (40 ± 34 vs 134 ± 34 )..lg/L, respectively)P6] Despite a wide interindividual variability, plasma concentrations remained lower throughout the sampling period (until 21 to 35 days), leading to significantly smaller AUCs in malnourished children. Peak plasma desethylchloroquine concentrations only attained 6 ± 4 )..lg/L in Kwashiorkor children compared to 50 ± 61 )..lg/L in healthy childrenJ96] Although differences in chloroquine binding were not assessed, other researchers did not find any difference in chloroquine binding to plasma proteins between healthy individuals and patients with KwashiorkorJ97] Since chloroquine half-life estimated from a month of blood sampling did not differ between both groups of children, a Kwashiorkor-induced reduction in chloroquine absorption is a probable explanation for the decreased plasma concentrations of both the parent and metabolite. 4.2 Elimination
Since chloroquine plasma or whole blood concentrations were not followed for extended periods of time, and because protein calorie malnourishment can affect drug metabolism,[98] malnutritioninduced variations in chloroquine metabolism cannot be ruled out. In malnourished mice the rate of metabolism of chloroquine was reduced. L99 ] In view of the inhibiting properties of antimalarial agents on drug metabolism and the widespread use © Adis International Limited. All rights reserved.
of drug combinations against resistant strains or concomitant infections, metabolic interactions are likely to occur, and their clinical significance should be investigated. 5. Clinical Pharmacokinetics in Different Ethnic Groups
The assessment of the relative importance of the 3 variables, disease, nutrition and ethnic origin, is a difficult task. Genetic and environmental factors are often indistinguishable as diseases have geographical-dependent incidences, and different ethnic groups have typical diets and beverages. 5.1 Absorption and Distribution
In healthy Sudanese individuals, when chloroquine 600mg base was administered with local beverages (aradaib, karkadi and lemon), its bioavailability was considerably reducedPOOl Mean chloroquine peak plasma concentrations and AUCo-24h were decreased by 62 to 73%. Since the 3 selected beverages had a very acidic pH (2.2 to 2.6), reduced chloroquine concentrations could have resulted from decreased intestinal absorption. Increased renal excretion of ionised molecules would be unlikely to occur following a single dose of acidic beverage. Food was found to enhance chloroquine bioavailability in healthy Indian volunteers.[101] When individuals were given a typical Indian breakfast with their chloroquine tablets (600mg chloroquine base), mean chloroquine peak plasma concentrations andAUC O.12h were increased by 52 and 42%, respectively. As i~ Swedish individuals,[20] chloroquine bioavailability showed considerable interindividual variability.[101] With or without food, chloroquine peak plasma concentrations and AUCO-12h varied 3-fold between individuals. Since the later elimination phases were not followed and metabolite concentrations were not measured, the contribution of differences in hepatic metabolism to this variability remains unknown. Clin. Pharmacokinet. 1996 Oct; 31 (4)
266
Ducharme & Farinotti
5.2 Elimination
In healthy males from Africa,[102.103] Thailand,[S4] and Sweden,[20] plasma or blood chloroquine concentrations declined slowly. In Nigerians and Ghanians,[102,103] interindividual variability was very high (pharmacokinetic parameters varied 1.5- to 3-fold), partly because of the insufficient durations of sampling (28 days) leading to important extrapolations in AVCs. Comparing chloroquine pharmacokinetics iIi different ethnic groups from various study protocols is, therefore, impossible and could lead to biased interpretations. Chloroquine body disposition in Caucasians, Asians or Blacks sharing a common environment has never been investigated. In a recent study, chloroquine pharmacokinetics in a Black individual did not differ significantly from the mean parameters estimated from 17 Caucasians.[21] Hepatic oxidative metabolism, which is dependent upon genetic and environmental factors, is a major determinant of drug pharmacokinetics and pharmacodynamics.[61] While 7 to 10% of Caucasians are classified as CYP2D6 poor metabolisers, the frequency is significantly lower in Asians, with only 1% being poor metabolisers,f104] The percentage also appears to be lower in Blacks, ranging from 0 (among 137 participants)[105] to 8%,f106] Furthermore, in Asians and Blacks, CYP2D6 activity seems to be lower than in Caucasian individuals, since metabolic ratios were found to be lower,f61] Since CYP2D6 could be implicated in chloroquine metabolism, this might have important clinical significance. 6. Clinical Pharmacokinetics in Pregnancy and Lactation In chloroquine-sensitive endemic areas, chloroquine is the prophylactic drug of choice during pregnancy and lactation,fl,107] Available evidence suggests that chloroquine is not strongly teratogenic, and that malaria prophylactic dosages are well tolerated during pregnancy.[IOS,109] Since malaria may lead to maternal anaemia, low birthweights, and eventually, in areas with little or no © Adis International Limited, All rights reserved,
immunity, to maternal and fetal mortality,[l] malaria prophylaxis is imperative: any risk of adverse effects should be balanced against the risk of developing the disease. In vitro, the rate of transplacental transfer of chloroquine was found to be 10w.[lIO] In pregnant rabbits, both chloroquine and desethylchloroquine rapidly crossed the placenta.[lll] In 7 pregnant women who were given chloroquine 5 mg/kg intramuscularly during their second term of labour, chloroquine was detected in the umbilical cord blood within 2 to 10 hours of maternal treatment.[I07] Mean maternal blood concentrations did not differ from mean umbilical cord concentrations (arterial or venous). All women had normal uncomplicated deliveries and the neonates did not experience any untoward effects up to 1 month postchloroquine. r107] Earlier reports failed to detect any chloroquine in breast milk,[1l2] but the utilised analytical methods lacked the necessary sensitivity and specificity. More recent investigations have demonstrated that small amounts of chloroquine are excreted into human milk. Following the administration of a single chloroquine 300mg base dosage to lactating women, the milk: plasma ratio in AVCs ranged from approximately 2 to 4,f113] Following single oral doses of chloroquine 600mg, 24 hour milk: plasma concentration ratios approximated 7 for chloroquine and 2 for desethylchloroquine,f1l4] V sing peak milk concentrations and assuming a daily milk ingestion of lL by the infant, the maximum percentage of the maternal dose recovered in milk over 9 days was estimated at 0.7 to 4% of the matemalloading dose,f113.114] During long term treatment, steady-state chloroquine concentrations may be higher and might expose the infant to higher drug concentrations. After a 5-day treatment totalling 2.1g of chloroquine to a lactating woman, the maximum amount of chloroquine ingested by the infant was estimated at 2 mg/day, which would be insufficient to induce any pharmacological effect.[1l5] Clin, Pharmacokinet, 1996 Oct; 31 (4)
267
Clinical Pharmacokinetics and Metabolism of Chloroquine
7. PharmacokineticPharmacodynamic Relationships 7.1 Parent Drug
Following single doses, peak chloroquine plasma concentrations approximate 2 to 4 X 10-6 mollL(650 to 1300 IlglL) and 0.2 to 0.4 x lO-6 mollL (65 to 128 IlglL) following intravenous or oral administration, respectively.[2.20] For malaria prophylaxis, treatment begins 1 week before entering the malarious area and continues for 4 weeks after leaving;D] for malaria treatment, chloroquine may also be given for several weeksJl] The beneficial effects of chloroquine appear slowly in rheumatoid arthritis, within months of treatment initiation, and patients may subsequently take the drug for years to prevent disease progression. At an effective dosage of 250 mg/day, steadystate plasma concentrations are in the micromolar range, varying between 0.8 and 2 x 10-6 mol/L (250 to 650 IlglL). Effective plasma concentrations appear to be lower in malaria [around 10-8 to 10-7 mollL (3 to 32 IlglL)]J20] Over the years, several studies have attempted to relate drug concentrations and toxicity. Following intravenous administration, threshold plasma chloroquine concentrations for cardiovascular toxicity were found to approximate 1000 IlglL or 3 x 10-6 mollLP] For other symptoms such as diplopia, dysphagia, accommodation disturbances, fatigue, and dizziness, toxic plasma concentrations were estimated at 0.5 to 1.2 x 10-6 mol/LPO] Earlier studies noted adverse effects in 80% of the patients with serum concentrations exceeding 2.5 x 10-6 mollL, while no adverse effects were reported at concentrations lower than 1.25 x 10-6 mol/L.[5] . Newer administration regimens (e.g. slow intravenous infusions) are designed to reduce peak concentrations and hence avoid unwanted adverse effectsJ2.21] 7.2 Chloroquine Metabolites
Desethy1chloroquine appears to be as active as chloroquine in vitro against sensitive strains of P. jalciparum,[116,1l7] but significantly less active © Adis International Limited. All rights reseNed.
against resistant strainsJll7,118] The N-dealkylated metabolites, desethy1chloroquine, bisdesethylchloroquine, and 7 -chloro-4-aminoquinolone, have been implicated in chloroquine-induced heart failureJ1l9,120] Bisdesethy1chloroquine has even been reported to be more cardiotoxic than the parent drugJl20] Because of the extremely long half-lives of chloroquine and its metabolites, and the fact that metabolites are of toxicological and pharmacological importance, patients on long term chloroquine therapy should have blood concentrations of both parent and metabolites monitored.[48] 7.3 Chloroquine Resistance
Chloroquine-resistant P. jalciparum first appeared in the early 1960s, in Thailand and Columbia,l3,121] Resistant strains now pose serious practical difficulties in virtually all areas endemic for this parasite. Resistance can also spread to other classes of antimalarial agents, such as other 4aminoquinolines, quinine, mefloquine, pyrimethamine, proguanil, or sulphonamides.[l22] The situation is analogous to that observed in oncology, where cross-resistance among various families of anticancer drugs is relatively frequent. The biochemical basis of chloroquine resistance is not completely understood, but it appears that resistant strains accumulate the drug less efficiently than sensitive onesJ123] This could be due to an induced efflux of chloroquine, since resistant parasites have been found to release the antimalarial agent 40 to 50 times more rapidly than susceptible onesJ124] Some similarities were observed with the multiple drug resistance phenotype of cancer cellsJ118] Cancer cells displaying multi drug resistance (MDR) overexpress a high molecular weight glycoprotein, P-glycoprotein (Pgp), which acts as an efflux pump that transports drugs out of the cellsJl25] Verapamil, which has been shown to reverse multidrug resistance by inhibiting Pgp, slowed chloroquine release, increased its accumulation by resistant, but not by susceptible, strains of P. jalciparum,[125] and completely reversed chloroquine resistanceJ122] Similarly, diltiazem potentiClln. Pharmacokinet. 1996 Oct; 31 (4)
268
ated the in vitro efficacy of chloroquine and desethylchloroquine in resistant clones of P. Jalciparum, but did not affect their fractional inhibitory concentrations in chloroquine-sensitive clones.[118,126] Pgp is located on the apical surface of columnar epithelial cells of the colon and jejunum, proximal renal tubules, pancreatic and biliary ducts, and on the biliary canalicular front of hepatocytes.l l27 ) Interestingly, these sites are located where there is cell and tissue immunoreactivity for CYP3As.ll28) In doxorubicin-resistant cells, CYP-dependent enzyme activities were found to be strongly increased,[129) possibly altering the biotransformation of xenobiotics. High-dose cyclosporin for MDR modulation resulted in significant alteration of doxorubicin disposition and remarkable toxicity in all patients.l l30) The decreased doxorubicin clearance might have resulted from the ability of cyclosporin to interfere not only with Pgp but also with CYPs. Cyclosporin, as well as tamoxifen and verapamil, other MDR modulators, are metabolised via CYP3As.[74,13l-133] Quercetin and other flavonoids, in addition to being Pgp inhibitors,[134] are among the strongest CYP3A inhibitors.[ 1351 Strains of P. berghei have been found to contain CYP, and the activities of aryl hydrocarbon hydroxylases and aminopyrine N-demethylases were higher in chloroquine-resistant strains than in sensitive ones.[136) In mice infected with resistant P. berghei, parasitaemia levels were decreased by the coadministration of chloroquine with a CYP-inhibitor complex of copper-(lysineh.l1371 When given separately, chloroquine and the complex had no antimalarial effect.[137) Ndifor et al.l 138 ] suggested that. a enhanced metabolic deactivation of the antimalarial agent via CYP might be an alternate explanation of drug resistance. In vivo and in vitro, the CYP inhibitor cimetidine improved parasite susceptibility to chloroquine. Whereas cimetidine enhanced chloroquine susceptibility in 60% of the isolates, verapamil completely reversed resistance in all resistant isolates. These preliminary data suggest that chloroquine © Adis International Limited. All rights reserved.
Ducharme & Farinotti
deactivation may be partly responsible for the observed drug resistance. [138]
8. Stereoselective Pharmacokinetics and Pharmacodynamics 8.1 Pharmacodynamic Potency
In mice infected with P. vinckei or P. berghei, S( +)-chloroquine has an ED50 3.5 times lower than that of R(-)-chloroquine.l 139 ,140) However, in vitro studies did not detect any significant difference in potency between both enantiomers against sensitive and resistant P. Jalciparum strains, S( +)chloroquine being slightly more active against resistant parasites. [117 J This in vitro-in vivo discrepancy suggests that the stereo selectivity in chloroquine body disposition could be responsible for the observed differences in activity between both enantiomers in vivo. 8.2 In Vitro Protein Binding
Chloroquine binding to plasma proteins is stereoselective,l39.40] Protein binding was measured in vitro, by equilibrium dialysis[391 or by ultrafiltration[ 401 of spiked plasma, albumin and
Clinical Pharmacokinetics and Metabolism of Chloroquine
sibly into other tissues. On the sole basis of these findings, the R( - )-enantiomer of chloroquine, which is almost 2 times less protein bound than the S( +)-form, would be expected to have a larger Vd. 8.3 In Vivo Body Disposition 8.3. 1 Administration of the Racemate
In agreement with in vitro binding data, for 3 individuals who received a single oral dose of racemic chloroquine, the 24-hour plasma concentrations of unbound R(-)-chloroquine were higher than those of S(+)-chloroquine.l 143 ] R : S ratios of chloroquine concentrations in urine approximated unity while R : S ratios of desethylchloroquine concentrations were lower than 1. Similar results were found in patients with arthritis treated with multiple doses of oral racemic chloroquine. Since both enantiomers had a 10- to 24-hour renal clearance surpassing the glomerular filtration rate, the faster clearance of S( +)-chloroquine could be due to a higher degree of renal secretion compared to R( - )-chloroquine. For desethylchloroquine, the S(+) enantiomer also had a faster renal clearance, about 6.5 times higher than that of the R( - )-enantiomer. This could result from both a stereoselective metabolism, favouring the formation of S( +)-metabolites from S( +)-chloroquine (the chiral carbon atom being unaffected by desethylation), and a preferential renal excretion. As with chloroquine, the renal clearance of the S(+)-enantiomer of hydroxychloroquine was higher than that of R( - )-hydroxychloroquine. Although hydroxychloroquine appears to be slightly less renally excreted than chloroquine (20%[144] vs 50%,PS.20,45-47]) both aminoquinolines undergo comparable pharmacokinetics. The stereoselective pharmacokinetics of hydroxy chloroquine following single[144] and multiple doses[145] have been recently reported. In accordance with the results obtained for chloroquine, blood concentrations of R( - )-hydroxychloroquine were always higher than those of S( +)-hydroxychloroquine, while the S(+)forms of the metabolites were higher than those of the R(-)-forms.l144.145] The shorter elimination © Adis International Limited. All rights reserved.
269
half-life of the S-enantiomer therefore appears to be due, at least in part, to both a faster urinary excretion and an increased hepatic metabolism. 8.3.2 Administration of the Separate Enantiomers
Following the intramuscular administration of the separate enantiomers, S( +)-chloroquine was found to have a shorter elimination half-life than R( - )-chloroquine in the albino rabbit. The Senantiomer appeared to be preferentially metabolised, since over the 504-hour sampling period whole blood concentrations of S( +)-desethylchloroquine were always higher than those of R(-)desethylchloroquine.[146] The separate enantiomers of chloroquine were also given to 6 healthy volunteers according to a crossover design with a 3-month wash-out period.l 147 ] Capillary blood was sampled for 672 hours post-administration and whole blood drug concentrations were measured by achiral chromatography. Results were consistent with those obtained in animal studies, showing lower blood concentrations and a shorter elimination half-life for S( +)-chloroquine compared with R(- )-chloroquine (236 ± 25 vs 294 ± 34 hours, respectively). S(+)chloroquine had a larger but comparable Vd (V area , 4830 ± 1490 vs 3410 ± 720L, S vs R), while its total body clearance was significantly faster (14.22 ± 4.26 vs 8.16 ± 2.28 Llh, S vs R). Since the whole blood concentrations of the S( +)-forms of the main metabolite desethylchloroquine always exceeded those of the R(-)-forms, one can suggest a preferential metabolism of S( +)-chloroquine, in spite of unknown metabolite kinetics. 8.4 Clinical Consequences of Chirality
There are no data on the stereo selectivity of drug-drug interactions and on the possible clinical consequences on efficacy or toxicity of the preferential metabolism of 1 enantiomer. In vitro, both chloroquine enantioners showed comparable degrees ofCYP2D6 inhibition, with Ki values of 12.3 and 9.9 )lmol/L for S- and R-chloroquine, respectively.[55] Whether this holds true when the drug is given clinically requires investigation. It is, thereClin. Pharmacokinet. 1996 Oct; 31 (4)
270
Ducharme & Farinotti
fore, premature to conclude on the interaction potential of the individual enantiomers. In a recent report, S( +)-chloroquine was found to be a greater inhibitor of histamine N-methyltransferase than R(-)-chloroquine.[8 11 However, there is no known relationship between the inhibition of histamine N-methylation and chloroquine adverse effects, prohibiting any conclusion on the clinical significance of this finding. S( +)-chloroquine was found to be more active than R(-)-chloroquine in animals,f139. 1401 while its clearance was faster, its metabolites could be thereby possibly contributing to its overall efficacy. In addition, the S(+)-enantiomer of hydroxychloroquine was found to be less extensively taken up by rabbit ocular tissuesJ 1481 Hence, the administration of the pure S( +)-enantiomer could provide greater efficacy and lesser toxicity.
9. Conclusion Because of its narrow therapeutic range and the pharmacological activity of its metabolites, a careful assessment of chloroquine pharmacokinetics is necessary for its optimal clinical use. Recently developed high performance liquid chromatography methods, and particularly chiral assays, will allow a better characterisation of the complex pharmacokinetics of the enantiomers of chloroquine and its metabolites. Finally, the implementation of clinical drug monitoring would enable the identification of interindividual differences and avoid deleterious drug-drug interactions and inadequate concentrations.
Acknowledgements The Medical Research Council of Canada is acknowledged for fellowship assistance to Dr Julie Ducharme.
References
I. White NJ, Nosten F. Advances in chemotherapy and prophylaxis of malaria. CUIT Opin Infect Dis 1993; 6: 323-30 2. White NJ, Miller KD, Churchill FC, et al. Chloroquine treatment of severe malaria in children. Pharmacokinetics, toxicity, and new dosage recommendations. N Engl J Med 1988; 319: 1493-500 3. Bloland PB, Lackritz EM, Kazembe PN, et al. Beyond chloroquine: implications of drug resistance for evaluating malaria
© Adis International Limited. All rights reserved.
therapy efficacy and treatment policy in Africa. J Infect Dis 1993; 167: 932-7 4. Maksymovytch W, Russel AS. Antimalarials in rheumatology: efficacy and safety. Semin Arthritis Rheum 1987; 16: 206-21 5. Frisk-Holmberg M, Bergqvist Y, Domeij-Nyberg B, et al. Chloroquine serum concentration and side effects: evidence for dose-dependence kinetics. Clin Pharmacol Ther 1979; 25: 345-50 6. Frisk-Holmberg M, Bergqvist Y, Termond E. Further support for changes in chloroquine disposition and metabolism between a low and high dose. Eur J Clin Pharmacol 1985; 28: 721-2 7. Frisk-Holmberg M, Bergqvist Y. Chloroquine disposition in man. Br J Clin Pharmacol1982; 14 Suppl.: 624-6 8. Frisk-Holmberg M, Bergqvist Y, Termond E, et al. The single dose kinetics of chloroquine and its major metabolite desethy1chloroquine in healthy subjects. Eur J Clin Pharmacol 1984; 26: 521-30 9. Tett SE, Cutler DJ. Apparent dose-dependence of chloroquine pharmacokinetics due to limited assay sensitivity and limited sampling times. Eur J Clin Pharmacol1987; 31: 729-31 10. Gustafsson LL, Rombo L, Alvan G, et al. On the question of dose-dependent chloroquine elimination of a single oral dose. Clin Pharmacol Ther 1983; 34: 383-5 II. Gustafsson LL, Bergqvist Y, Ericsson 0, et al. Pitfalls in the measurement of chloroquine concentrations. Lancet 1983; I: 126 12. Adelusi SA, Salako LA. Improved fluorimetric assay of chloroquine in biological samples. J Pharm Pharmacol 1980; 32: 711-2 13. Alvan G, Ekman N, Lindstrom B. Determination of chloroquine and its desethyl metabolite in plasma, red blood cells and urine by liquid chromatography. J Chromatogr 1982; 229: 241-7 14. Geary TG, Akood MA, Jensen JB. Characteristics of chloroquine binding to glass and plastic. Am J Trop Med Hyg 1983; 32: 19-23 15. McChesney EW, Fasco MG, Banks WF. The metabolism of chloroquine in man during and after repeated oral dosage. J Pharmacol Exp Ther 1967; 158: 323-31 16. Bergqvist Y, Domeij-Nyberg B. Distribution of chloroquine and its major metabolite desethyl-chloroquine in human blood cells and its implication for the quantitative determination of these compounds in serum and plasma. J Chromatogr 1983; 272: 137-48 17. French JK, Hurst NP, O'Donnell ML, et al. Uptake of CQ and HCQ by human blood leucocytes in vitro: relation to cellular concentrations during antirheumatic therapy. Ann Rheum Dis 1987; 46: 42-5 18. McChesney EW, Conway WD, Banks WF, et al. Studies of the metabolism of some compounds of the 4-amino-7-chloroquine series. J Pharm Exp Ther 1966; 151: 482-93 19. Krishna S, White NJ. Pharmacokinetics of quinine, chloroquine and amodiaquine: clinical implications. Clin Pharmacokinet 1996; 30: 263-99 20. Gustafsson LL, Walker O. Alvan G, et al. Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol1983; 15: 471-9 21. De Vries PJ, Oosterhuis B, Van Boxtel CJ. Single-dose pharmacokinetics of chloroquine and its main metabolite in healthy volunteers. Drug Invest 1994; 8: 143-9 22. Wetsteyn JCFM, De Vries PJ, Oosterhuis B, et al. The pharmacokinetics of three multiple dose regimens of chloroquine:
Clln. Pharmacoklnet. 1996 Oct: 31 (4)
Clinical Pharmacokinetics and Metabolism of Chloroquine
implications for malaria chemoprophylaxis. Br 1 Clin Pharmacol 1995; 39: 696-9 23. Rombo L, Ericsson 0, Alvan G, et al. Chloroquine and desethylchloroquine in plasma, serum, and whole blood: problems in assay and handling of samples. Ther Drug Monit 1985; 7: 211-5 24. McChesney EW, Shekosky JM, Hernandez PH. Metabolism of chloroquine-3- 14(: in the rhesus monkey. Biochem Pharmacol 1967; 16: 2444-7 25. Grundmann M, Mikulikova I, Vrublovsky P. Tissue distribution of subcutaneously administered chloroquine in the rat. Arzneimittelforschung 1971; 21: 573-4 26. MacKenzie AH. Pharmacologic actions of 4-aminoquinoline compounds. Am J Med 1983; 75 Suppl. I: 5-10 27. Robinson AE, Coffer AI, Camps FE. The distribution of chloroquine in man after fatal poisoning. 1 Pharm Pharmacol 1970; 22: 700-3 28. Larsson B, Tjalve H. Studies on the mechanism of drug-binding to melanin. Biochem Pharmacol 1979; 28: 1181-7 29. Thompson PE, Werbel LM. Antimalarial agents. New York: Academic Press, 1972: 150-96 30. Titus EO. Recent developments in the understanding of the pharmacokinetics and mechanism of action of chloroquine. Ther Drug Monit 1989; 11: 369-79 31. Yayon A, Cabantchick ZI, Ginsberg H. Identification of the acidic compartment of Plasmodium falciparum-infected erythrocytes as the target of the antimalarial drug chloroquine. EMBO 1 1984; 3: 2695-700 32. Keen JH, Willingham MC, Pastan IH. Clathrin-coated vesicles: isolation, dissociation, and factor-dependent reassociation of clathrin baskets. Cell 1979; 16: 303-12 33. Ferrari V, Cutler DJ. Kinetics and thermodynamics of chloroquine and hydroxychloroquine transport across the human erythrocyte membrane. Biochem Pharmacol 1991; 40: 23-30 34. Macintyre AC, Cutler D1. The potential role of Iysosomes in tissue distribution of weak bases. Biopharm Drug Dispos 1988; 9: 5 \3-26 35. Veignie E, Moreau S. The mode of action of chloroquine. Nonweak base properties of 4-aminoquinolines and antimalarial effects on strains of Plasmodium. Ann Trop Med Parasitol 1991; 85: 229-37 36. Krogstad DJ, Schlessinger PH, Gluzman IY. Antimalarials increase vesicle pH in Plasmodium falciparum. 1 Cell BioI 1985; 10 1: 2302-9 37. Moreau S, Prensier G, Maalla 1, et al. Identification of distinct accumulation sites of 4-aminoquinoline in chloroquine sensitive and resistant Plasmodium berghei strains. Eur 1 Cell BioI 1986;42:207-10 38. Augustjins P, Geusens P, Verbeke N. Chloroquine levels in blood during chronic treatment of patients with rheumatoid arthritis. Eur 1 Clin Pharmacol 1992; 42: 429-33 39. Ofori-Adjei D, Ericsson 0, Lindstrom B, et al. Protein binding of chloroquine enantiomers and desethylchloroquine. Br 1 Clin Pharmacol1986; 22: 356-8 40. Augustijns P, Verbeke N. Stereoselective pharmacokinetic properties of chloroquine and de-ethyl-chloroquine in humans. Clin Pharmacokinet 1993; 24: 259-69 41. Walker 0, Birkett D1, Alvan G, et al. Characterization of chloroquine plasma protein binding in man. Br J Clin Pharmacol 1983; 15: 375-7 42. Gustafsson LL, Lindstrom B, Grahnen A, et al. Chloroquine excretion following malaria prophylaxis. Br J Clin Pharmacol 1987; 24: 221-4
© Adis International Limited. All rights reserved.
27l
43. Ofori-Adjei D, Ericsson 0. Chloroquine in nail clippings [letter]. Lancet 1985; II: 331 44. Frisk-Holmberg M, Bergqvist Y, Termond E. Further support for changes in chloroquine disposition between a low and a high dose. Eur 1 Clin Pharmacol 1985; 28: 721-2 45. Frisk-Holmberg M, Bergqvist Y, Domeij-Nyberg B. Steadystate disposition of chloroquine in patients with rheumatoid disease. Eur 1 Clin Pharmacol 1983; 24: 837-9 46. Frisk-Holmberg M, Bergqvist Y, Termond E, et al. The single dose kinetics of chloroquine and its major metabolite desethyl-chloroquine in healthy subjects. Eur 1 Clin Pharmacol 1984; 26: 521-30 47. Price-Evans DA, Fletcher KA, Baty ID. The urinary excretion of chloroquine in different ethnic groups. Ann Trop Med Parasitol 1979; 73: 11-7 48. Ette EI, Essien EE, Thomas WOA, et aI. Pharmacokinetics of chloroquine and some of its metabolites in healthy volunteers: a single dose study. 1 Clin Pharmacol 1989; 29: 457-62 49. Bennett WM, Aronoff GR, Golper TA, et al. Drug prescribing in renal failure. Philadelphia: American College of Physicians, 1987 50. Hellgren U, Alvan G, Jerling M. On the question of interindividual variations in chloroquine concentrations. Eur J Clin Pharmacol 1995; 45: 383-5 51. Bergqvist Y, Frisk-Holmberg M. Sensitive method for the determination of chloroquine and its metabolite desethylchloroquine in human plasma and urine by high performance liquid chromatography. 1 Chromatogr 1980; 221: 119-27 52. Augustijns P, Verbeke N. HPLC method for the determination of chloroquine and its main metabolite in biological samples. 1 Liq Chromatogr Clin Analysis 1990; 13: 1203-13 53. Adelusi SA, Salako LA. Tissue and blood concentrations of chloroquine following chronic administration in the rat. J Pharm Pharmacol 1982; 34: 733-5 54. Lancaster DL, Adio RA, Tai KK, et al. Inhibition of metoprolol metabolism by chloroquine and other antimalarial drugs. 1 Pharm Pharmacol1990; 42: 267-71 55. Masimirembwa CM, Hasler JA, 1ohansson 1. Inhibitory effects of antiparasitic drugs on cytochrome P450 2D6. Eur 1 Clin Pharmacol 1995;48: 35-8 56. Halliday RC, Jones BC, Smith DA, et al. An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems. Br J Clin Pharmacol 1995; 40: 369-78 57. Koymans L, Vermeulen NPE, van Acker SABE, et al. A predictive model for substrates of cytochromes P450-debrisoquine (2D6). Chern Res Toxico11992; 5: 211-9 58. Mikus G, Ha AR, Vozeh S, et al. Pharmacokinetics and metabolism of quinidine in extensive and poor metabolisers of sparteine. Eur 1 Clin Pharmacol 1986; 31: 69-72 59. Evans DA, Mahgoub A, Sloan TP, et al. A family and population study of the genetic polymorphism of debrisoquin oxidation in a white British population. 1 Med Genet 1980; 17: 102-5 60. Eichelbaum M, Gross AS. The genetic polymorphism of debrisoquine/sparteine metabolism, clinical aspects. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992: 625-48 61. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation: current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet 1995; 29: 192-209 62. Daniel W, Netter K1. Alteration of cytochrome P450 by prolonged administration of imipramine and/or lithium to rats.
Clin. Pharmacokinet. 1996 Oct; 31 (4)
272
Naunyn Schmiedebergs Arch Exp Pathol Pharmacol 1990; 342: 234-40 63. Masubichi Y, Takahashii C, Fujio N, et al. Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats. Drug Metab Dispos 1995; 23: 999-1003 64. Onyeji CO, Toriola TA, Ogunbona FA. Lack of pharmacokinetic interaction between chloroquine and imipramine. Ther Drug Monit 1993 ; 15: 43-6 65. Masimirembwa CM, Gustafsson LL, Dahl ML, et al. Lack of effect of chloroquine on the debrisoquine (CYP2D6) and Smephenytoin (CYP2CI9) hydroxylation phenotypes. Br J Clin Pharmacol1996; 41: 344-6 66. Ette EI, Brown-Awala EA, Essien EE. Chloroquine elimination in humans: effect of low-dose cimetidine. J Clin Pharmacol 1987; 27: 813-6 67. Knodell RG, Holtzman lL, Crankshaw DL, et al. Drug metabolism by rat and human hepatic microsomes in response to interaction with H2-receptor antagonists. Gastroenterology 1982; 82: 84-8 68. Ortiz de Montellano PR, Reich NO. Inhibition of cytochrome P-450 enzymes. In: Ortiz de Montellano PR, editor. Cytochrome P-450: structure, mechanism and biochemistry. New York: Plenum, 1986: 273-314 69. Knodell RG, Browne DG, Gwozdz GP, et al. Differential inhibition of individual human liver cytochromes P-450 by cimetidine. Gastroenterology 1991; 101: 1680-91 70. Ette EI, Brown-Awala EA, Essien EE. Effect of ranitidine on chloroquine disposition. Drug Intell Clin Pharm 1987; 21: 732-4 71. Klotz U, Kroemer HK. The drug interaction potential of rani tidine: an update. Pharmacol Ther 1991; 50: 233-44 72. Nampoory MRN, Nessim 1, Gupta RK, et al. Drug interaction of chloroquine with ciclosporin. Nephron 1992; 62: 108-9 73. Filniez P, Gendoo Z, Chuet C, et al. Interaction between cyclosporin and chloroquine. Nephron 1993; 65: 33 74. Combalbert J, Fabre I, Fabre G, et al. Metabolism of cyclosporin: IV-Purification and identification ofthe rifampicin-inducible human liver cytochrome P-450 (cyclosporin oxidase) as a product of P450IIIA gene subfamily. Drug Metab Bioi Fate Chem 1989; 17: 197-207 75. Kolars lC, Schmiedlin-Ren P, Schuetz JD, et al. Identification of rifampicin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. 1 Clin Invest 1992; 90: 1871-8 76. Mwankwo 10, Garba MA, Chinje CE, et al. Possible chloroquine-induced modification of N-acetylation of isoniazid and sulphadimidine in the rat. Biochem Pharmacol 1990; 40: 654-9 77. Svensson CK, Zaher H, Tomilo M. Disposition of sulfamethazine and N-acetylsulfamethazine in the rat. Pharm Res 1991; 8: 1069-70 78. Lindsay RM, Baty ID. The effect of streptozotocin-induced diabetes on the in vivo acetylation capacity and the in vitro blood N-acetyltransferase activity of the adult male SpragueDawley rat. Biochem Pharmacol 1990; 39: 1193-7 79. Svensson CK, Drobitch RK, Tomilo M. Effects of chloroquine and primaquine on rat liver cytosolic N-acetyltransferase activity. Biochem Pharmacol1991; 42: 954-6 80. Pacifici DM, Donatelli P, Giuliani L. Histamine N-methyltransferase: inhibition by drugs. Br 1 Clin Pharmacol 1992; 34: 322-7 81. Donatelli P, Marchi G, Giuliani L, et al. Stereoselective inhibition by chloroquine of histamine N-methyltransferase in the human liver and brain. Eur 1 Clin Pharmacol1994; 47: 345-9
© Adis International Limited. All rights reserved.
Ducharme & Farinotti
82. Adelusi SA, Dawodu AH, Salako L. Kinetics of the uptake and elimination of chloroquine in children with malaria. Br J Clin Pharmacol 1982; 14:483-7 83. Walker 0, Dawodu AH, Adeyokunnu AA, et al. Plasma chloroquine and desethy1chloroquine concentrations in children during and after chloroquine treatment for malaria. Br 1 Pharmaco11983 ; 16: 701-5 84. Na-Bangchang K, Limpaibul L, Tan-Ariya ATP, et al. The pharmacokinetics of chloroquine in healthy Thai subjects and patients with Plasmodium vivax malaria. Br J Clin Pharmacol 1994; 38: 278-81 85. Edwards G, Looareesuwan S, Davies A, et al. Pharmacokinetics of chloroquine in Thais: plasma and red cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria. Br 1 Clin Pharmacol 1988; 25: 477-85 86. White NJ, Looareesuwan S, Warrell SA, et al. Quinine pharmacokinetics and toxicity in cerebral and uncomplicated fa1ciparum malaria. Am 1 Med 1982; 73: 564-71 87. Warhurst DC. The quinine-haemin interaction and its relationship to antimalarial activity. Biochem Pharmacol 1981; 30: 3323-7 88. White NJ. Clinical pharmacokinetics of antimalarial drugs. Clin Pharmacokinet 1985; 10: 187-215 89. Silamut K, Molunto P, Ho M, et al. ai-Acid glucoprotein (orosomucoid) and plasma protein binding of quinine in fa1ciparum malaria. Br J Clin Pharmacol 1991; 32: 311-5 90. White Nl, Watt G, Bergqvist Y, et al. Parenteral chloroquine for treating fa1ciparum malaria. 1 Infect Dis 1987; 155: 192-201 91. Trenholme GM, Williams RL, Rieckmann KH, et al. Quinine disposition during malaria and during induced fever. Clin Pharmacol Ther 1976; 19: 459-67 92. Skirrow MR, Chongsuphajaisiddhi T, Maegraith BG. The circulation in malaria. II. Portal angiography in monkeys (Macaca mulatta) with P. knowlesi and in shock following manipulation of the gut. Ann Trop Med Parasitol 1964; 58: 502-10 93. Aikawa M, Susuki M, Gutierrez Y. Pathology of malaria. In: Kreier JP, editor. Malaria. Vol 2. New York: Academic Press, 1980: 47-102 94. Verdier F, Clavier F, Deloron P, et al. Distribution de la chloroquine et de la desethy1chloroquine dans Ie sang, Ie plasma et les erythrocytes de sujets sains et paludeens. Pathol Bioi 1984; 32: 359-61 95. Tulpule A, Krishnaswamy K. Chloroquine kinetics in the undernourished. Eur 1 Clin Pharmacol1983; 24: 273-6 96. Walker 0, Dawodu AH, Salako LA, et al. Single dose disposition of chloroquine in Kwashiorkor and normal children-evidence for decreased absorption in Kwashiorkor. Br 1 Clin Pharmacol 1987; 23: 467-2 97. Buchanan H, Van der Walt LA. The binding of chloroquine to normal and Kwashiorkor serum. Am 1 Trop Med Hyg 1977; 26: 1025-7 98. Koizumi A, Weindruch R, Walford RI. Influences of dietary restriction and age on liver enzyme activities and lipid peroxidation in mice. J Nutr 1987; 117: 361-5 99. Adelusi SA. Urinary levels of chloroquine in relation to dietary protein. Experientia 1982; 38: 1326-7 100. Mahmoud BM, Ali HM, Homeida MA, et al. Significant reduction in chloroquine bioavailability following coadministration with the Sudanese beverages Aradaib, Karkadi and Lemon. J Antimicrob Chemother 1994; 33: 1005-9 101. Tulpule A, Krishnaswamy K. Effect of food on bioavailability of chloroquine. Eur J Clin Pharmacol 1982; 23: 271-3
Clin. Pharmacokinet. 1996 Oct; 31 (4)
Clinical Pharmacokinetics and Metabolism of Chloroquine
102. Fadeke-Aderounmu A, Salako LA, Lindstrom B, et al. Comparison of the pharmacokinetics of chloroquine after single intravenous and intramuscular administration in healthy Africans. Br J Clin Pharmacol 1986; 22: 559-64 \03. Adjepon-Yamoah KK, Ofori-Adjei D, Woolhouse NM, et al. Whole blood single-dose kinetics of chloroquine and desethylchloroquine in Africans. Ther Drug Monit 1986; 8: 195-9 \04. Bertilsson L, Lou YQ, Du YL, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquine and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388-97 105. Iyun AO, Lennard MS, Tucker GT, et al. Metoprolol and debrisoquine metabolism in Nigerians: lack of evidence for polymorphic oxidation. Clin Pharmacol Ther 1986; 40: 387-94 106. Mbanefo, C, Bababunmi EA, Mahgoub A, et al. a study of the debrisoquine hydroxylation polymorphism in a Nigerian population. Xenobiotica 1980; \0: 811-8 107. Akintonwa A, Gbajumo SA, Biola Mabadeje AE Placental and milk transfer of chloroquine in humans. Ther Drug Monit 1988; \0: 147-9 \08. Levy M, Buskila D, Gladman DD, et al. Pregnancy outcome following first trimester exposure to chloroquine. Am J Perinatol 1991; 8: 174-8 \09. Wolfe MS, Cordero JE Safety of chloroquine in chemosuppression of malaria during pregnancy. BMJ 1985; 290: 1466-7 110. Leng JJ, Mbanzulu PN, Akbaraly JP, et al. Etude in vitro du passage transplacentaire du sulfate de chloroquine. Pathol Bioi 1987; 35: \051-4 III. Akintonwa A, Meyer MC, Yau KT. Placental transfer of chloroquine in pregnant rabbits. Res Commun Chem Pathol Pharmaco11983; 40: 443-55 112. 0 ' Brien TE. Excretion of drugs in human milk. Am J Hosp Pharm 1974; 31: 844-54 113. Edstein MD, Veenendaal JR, Newman K, et a!. Excretion of chloroquine, dapsone and pyrimethamine in human milk. Br J Clin Pharmacol 1986; 22: 733-5 114. Ogunbona FA, Onyeji CO, Bolaji 00, et al. Excretion of chloroquine and desethylchloroquine in human milk. Br J Clin Pharmacol 1987; 23: 473-6 115. Deturmeny E, Viala A, Durand A et al. Le passage de la chloroquine dans Ie lait, sur I cas. Therapie 1984; 39: 438-40 116. Fadeke-Aderounmu A. In vitro assessment of the antimalarial activity of chloroquine and its major metabolites. Ann Trop Med Parasitol 1984; 78: 581 117. Fu S, Bjorkman, Wahlin B, eta!' In vitro activity of chloroquine, the two enantiomers of chloroquine, desethylchloroquine and pyronaridine against Plasmodium falciparum. Br J Clin Pharmacol 1986; 22: 93-6 118. Kyle DE, Oduola AMJ , Martin SK, et al. Plasmodium falciparum: modulation by calcium antagonists of resistance to chloroquine, desethy\Chloroquine, quinine and quinidine in vitro. Trans R Soc Trop Med Hyg 1990; 84: 474-8 119. Ladipo GOA, Essien EE, Andy JJ. Complete heart block in chronic chloroquine poisoning. Int J Cardio11983; 4: 198-200 120. Essien EE, Ette EI. Effects of chloroquine and desethylchloroquine on rabbit myocardium and mitochondria. J Pharm Pharmacol 1986; 38: 833-40 121. Peters W. The prevention of antimalarial drug resistance. Pharmacol Ther 1990; 47: 488-508 122. Martin SK, Oduola AMJ, Milhous WK. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 1987; 235: 899-901
© Adis International Limited. All rights reserved.
273
123. Yayon A, Cabantchik ZI, Ginsburg H. Susceptibility of human malaria parasites to chloroquine is pH dependent. Proc Natl Acad Sci USA 1985; 82: 2784-8 124. Krogstad DJ, Gluzman IY, Kyle DE, et al. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 1987; 238: 1283-5 125. Pastan I, Gottesman M. Multiple-drug resistance in human cancer. N Engl J Med 1987; 316: 1388-93 126. Martiney JA, Cerami A, Slater AFG. Verapamil reversal of chloroquine resistance in the malaria parasite Plasmodium fa\Ciparum is specific for resistant parasites and independent of the weak base effect. J BioI Chem 1995; 270: 22393-8 127. Thiebaut F, Tsuruo T, Hamada H, et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987; 84: 7735-8 128. Murray GI, Barnes TS, Sewell HF, et al. The immunocytochemicallocalization and distribution of cytochrome P-450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br J Clin Pharmacol 1988; 25: 465-75 129. Cowan KH, Batist G, Tulpule A, et al. Similar biochemistry changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats. Proc Nat! Acad Sci USA 1986; 83: 9328-32 130. Rushing DA, Raber SR, Rodvold KA, et al. The effects of cyclophosphamide on the pharmacokinetics of doxorubicin in patients with small cell lung cancer. Cancer 1994; 74: 834-41 131. Kronbach T, Fischer V, Meyer UA, et al. Cyclosporin metabolism in human liver: identification of a cytochrome P450IlI gene family as the major cyclosporin-metabolizing enzyme explains interactions of cyclosporin with other drugs. Clin Pharmacol Ther 1988; 43: 630-5 132. Mani C, Gelboin HV, Park SS, et a!. Metabolism of the antimammary cancer anti estrogenic agent tamoxifen. I. Cytochrome P-450-catalyzed N-demethylation and 4-hydroxylation. Drug Metab Dispos 1993; 21: 645-56 133. Jacolot F, Simon I, Dreano Y, et al. Identification of the cytochrome P450 IlIA family as the enzymes involved in the Nde methylation of tamoxifen in human liver microsomes. Biochem Pharmacol 1991; 41: 1911-9 134. Scambia G, Ranelleti FO, Panici PB, et al. Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast cancer cell line; P-glycoprotein as a possible target. Cancer Chemother Pharmacol 1994; 34: 459-64 135. Rashid J, McKinstry C, Renwick AG, et al. Quercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juice. Br J Clin Pharmacol 1993; 36: 460-3 136. Salganik RI, Pankova TG, Chekhonadskiku TW, et al. Chloroquine resistance of Plasmodium berghei: biochemical basis and counter measures. Bull World Health Organ 1987; 65: 381-6 137. Rabinovich SA, Kulikovskaya 1M, Maksakovskaya EV, et al. Suppression of the chloroquine resistance of Plasmodium berghei by the treatment of infected mice with microsomal monooxygenase inhibitor. Bull World Health Organ 1987; 65: 387-9 138. Ndifor AM, Howells RE, Bray PG, et a!. Enhancement of drug susceptibility in Plasmodium fa\Ciparum in vitro and Plasmodium berghei in vivo by mixed-function oxidase inhibitors. Antimicrob Agents Chemother 1993; 37: 1318-23 139. Von Fink E, Minet G, Nickel P. Chloroquine enantiomers, activity against P. vinckei and binding on DNA. Arzneimittel Forschung 1979; 29: 163-4
Clin. Pharmacokinet. 1996 Oct; 31 (4)
274
140. Haberkorn A, Kraft HP, Blaschke G. Antimalarial activity in animals of the optical isomers of chloroquine diphosphate. Tropenmed Parasitol 1979; 30: 308-12 141. McLachlan AJ, Cutler DJ, Tett SE. Plasma protein binding of the enantiomers of hydroxychloroquine and metabolites. Eur J Clin Pharmacol 1993; 44: 401-4 142. Brocks DR, Skeith KJ, Johnston C, et aL Hematologic disposition of hydroxychloroquine enantiomers. J Clin Pharmacol 1994: 34: 1088-97 143. Ofori-Adjei D, Ericsson 0, Lindstrom B, et aL Enantioselective analysis of chloroquine and desethylchloroquine after oral administration of racemic chloroquine. Ther Drug Monit 1986; 8: 457-61 144. Ducharme J, Fieger H, Ducharme MP, et aL Enantioselective disposition of hydroxychloroquine after a single oral dose of the racemate to healthy subjects. Br J Clin Pharmacol 1995; 40: 127-33 145. McLachlan AJ, Tett SE, Cutler OJ, et aL Disposition of the enantiomers of hydroxychloroquine in subjects with rheuma-
Ducharme & Farinotti
toid arthritis following multiple doses of the racemate. Br J Clin Pharmacol 1993; 36: 78-81 146. Augustijns P, Verbeke N. Stereoselectivity in the disposition of chloroquine and desethylchloroquine in rabbits. Arzneimittel Forschung 1992; 42: 825-8 147. Augustijns P, Geusens P, Verbeke N. Chloroquine pharmacokinetic data during chronic daily treatment [reply to the letter by McLachlan et aLl. Eur J Clin Pharmacol 1993; 44: 409-10 148. Wainer I, Chen JC, Parenteau HI, et aL Distribution of the enantiomers of hydroxychloroquine and its metabolites in ocular tissues of the rabbit after oral administration of racemic hydroxychloroquine. Chirality 1994; 6: 347-54
Correspondence and reprints: Dr Robert Farinotti, Service de Pharmacie Clinique, Faculte de Pharmacie, 5 rue JeanBaptiste Clement, 92290 Chatenay-Malabry, France.
Errata
Vol. 31, No.1, page 12: In column 2, paragraph 2, line 7, the reference numbers should read [31,36], not [31,33]. Vol. 31, No.1, page 20: In column 2, paragraph 3, line 7, the reference number should read [126], not [120]. [Andersson T. Pharmacokinetics, metabolism amd interactions of acid pump inhibitors: focus on omeprazoie, iansoprazoie and pantoprazoie. c/in Pharmacokinet 1996 Jui; 31 (1): 9-28J.
© Adis International limited, All rights reserved,
Clin. Pharmacokinet, 1996 Oct; 31 (4)