Clln Pharmacoklnet. 28 (6) 449-457,1995 0312-5963/95/0006-0449/$04.50/0

DRUG DISPOSITION

© Adis International limited . All rights reserved.

Clinical Pharmacokinetics of Tacrine Stephen Madden, Vanessa Spaldin and B. Kevin Park Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, England

Contents Summary . .. .. . 1. Analytical Methods 2. Pharmacokinetics . 2.1 Absorption, Bioavailability and Distribution 2.2 Metabolism and Elimination . . . . . . 2.3 Nonlinear Pharmacokinetics . . . . . 3. Efficacy of Tacrine in Alzheimer's Disease. 4. Tolerability . . . . . 5. Drug Interactions . 6. Conclusions . . . .

Summary

449

450 450 450 451 452 452 454 454 455

Tacrine is currently the only treatment approved for use in Alzheimer's disease. There is, however, considerable debate over its effectiveness due to conflicting clinical trial results. Most investigators agree, nevertheless, that a definite sub-population of patients do benefit from therapy with tacrine. Tacrine is associated with large pharmacokinetic interindividual variation within both patient and control groups. This is thought to influence both the efficacy and incidence of symptomatic adverse effects in individual patients. Following oral administration of tacrine the drug is rapidly and well absorbed with peak plasma concentrations (Cmax) achieved within O.S to 3 hours (after a single dose of 20 to SOmg). Tacrine appears to have a wide tissue distribution, which is reflected by its large volume of distribution. High concentrations of the drug were found in the kidney, liver, adrenal gland and brain tissue in animal models. It has a low bioavailability following oral intake, thought to result from extensive first-pass metabolism. Bioavailability can be increased upon rectal administration. The drug is rapidly and extensively metabolised in humans. In vitro metabolism studies have demonstrated the importance of cytochrome P4S0 (CYPIA2) in the biotransformation of tacrine to 1-,2-,4- and 7-hydroxylated metabolites. In humans, mono- and dihydroxylated tacrine and glucuronide conjugates were identified in the urine, which was the primary route of excretion. The elimination half-life of tacrine was short, I.S to 2.S hours after single oral and intravenous doses and 2.9 to 3.6 hours after multiple oral doses. At low doses (lOmg) of tacrine, the pharmacokinetic profile was nonlinear and the oral bioavailability of the drug was disproportionately low in comparison to higher doses of tacrine (20mg). This may reflect saturable hepatic uptake of the parent compound. Both symptomatic and asymptomatic adverse effects occur frequently with

450

Madden et al.

tacrine therapy (32 to 80% of patients). These adverse reactions, ranging from predictable cholinergic effects to nonpredictable elevations in serum transaminase levels, can however be reversed by dosage withdrawal and/or adjustment. It has been postulated that the elevated levels of transaminase associated with tacrine therapy in vivo are dependent upon bioactivation of tacrine, mediated by hepatic CYPIA2, to form a toxic compound. Limited data are available regarding the propensity of tacrine to interact with other drugs. In one study, concomitant administration of theophylline led to an alteration of the pharmacokinetics of theophylline, whereas an elevation of plasma tacrine concentrations results from coadministration of cimetidine. Both of these effects are thought to be due to the interaction of the agents with CYPI A2. Therefore, the potential for tacrine to be subject to interactions with other drugs that are substrates of this enzyme should be recognised.

Tacrine was first marketed in the 1940s in combination with morphine to lessen respiratory depression without affecting analgesia.[1] It has since been widely used in a variety of clinical situations, such as management of pain in terminal cancer,[2] myasthenia gravis,[3] antidepressant overdose[4] and as an agent that prolongs the elimination half-life of suxamethonium choline (succinyl choline).l5] Gershon[6] noted the ability of tacrine to reverse the state of delirium induced by glycolate psychomimetic drugs such as N-ethyl-3-piperidyl-2cyclopentyl-2-phenoglycolate. In the 1980s the anticholinesterase activity of tacrine led to interest in its possible use in the treatment of Alzheimer's disease[7] and other disorders where cholinergic hypofunction is thought to be of clinical significance.l8] More recently, Fredj et aLl91 have investigated the efficacy of tacrine in the treatment ofHIY.

1. Analytical Methods High performance liquid chromatography (HPLC) with ultraviolet or fluorescence detection is most commonly used for the determination of tacrine in serum or plasma.[8,1O-13] Forsyth et aLl13] described a simple method employing chloroform extraction and fluorescent detection (excitation wavelength 330nm, emission wavelength 365nm) which has a lower limit of detection of 0.2 f..I.g/L tacrine. Chromatographic separation was performed on a Shendon hypersil50DS column (25 x 0.5cm) © Adis International Limited. All rights reserved.

and a mobile phase of methanol/H20/triethylamine (pH 5.0). The coefficients of variation (CVs) for 1, 5 and 20 f..I.glL tacrine were 8.5, 2.2 and 3.0%, respectively. Interassay variation for 5 f..I.glL tacrine was 5.0%. Several investigators[8,1O] have employed the method of Ekman et al.l 12] that, by use of ultraviolet detection at 240nm, facilitates the determination of both tacrine and its I-hydroxy metabolite in plasma. Separation is achieved using a nucleosil 5C 18 column (15 x 0.46cm) and a mobile phase of acetonitrile/O.02 mol/L phosphate buffer (pH 2.7). The detection limit for both compounds was 0.3 f..I.glL, and the CVs were 2.7 and 4.0% for 5 f..I.glL of tacrine and I-hydroxy-tacrine, respectively.

2. Pharmacokinetics The pharmacokinetic properties of tacrine have been determined in a range of patient and control groups (table I). Large interindividual differences in the pharmacokinetic profile of tacrine exist, and these are thought to have an effect on both therapeutic efficacy and adverse reactions in individual patients.[15,16] 2.1 Absorption, Bioavailability and Distribution

Tacrine is well absorbed from the gastrointestinal tract after oral administration, due to its lipophilic nature.[8,17,18] Hartvig et aLl8] have described C lin. Pharmacokinet. 28 (6) 1995

451

Tacrine Pharmacokinetics

the pharmacokinetics of tacrine following oral administration of a single 25mg dose in patients with amyotrophic lateral sclerosis. The absorption halflife was rapid and varied between 10 and 37 minutes after oral administration. Large interindividual differences in time to reach peak plasma concentration (t max ) and area under the plasma concentration-time curve (AVC) were seen. Peak plasma concentrations of tacrine (C max ) of less than 15 f.LglL were achieved 0.5 to 3 hours postdose. When the AVC data after oral and intravenous administration were compared, oral bioavailability was found to be low, ranging from 5.5 to 36% (mean 17.4 ± 13.1 %) in the 4 patients studied. This low bioavailability may be explained by extensive first-pass metabolism, which results in the presence of metabolites in the plasma soon after administration. After 7 weeks of administration of tacrine 175 to 200 mg/day, Cmax values at steady-state ranged from 3.3 to 167 f.LglL (mean 60.0 ± 74 f.LglL). Ahlin et al.[lO] and Cutler et aUll] have reported similar data in patients with Alzheimer's disease, as have Selen et al.,[14] in healthy volunteers. In the study of Ahlin et al.,[IO] 3 patients were administered tacrine by both oral and rectal routes. In all 3 patients, bioavailability was increased from 6, 10 and 3% after oral administration to 39, 54 and 28% after rectal administration, respectively. The volume of distribution (Vd) of tacrine at steadystate was high, ranging from 260 ± 132UIO] to 349 ± 193U8] with intravenous doses of 15 and 30mg, respectively. Table I. Mean pharmacokinetic parameters after oral administration

01 a single dose of tacrine 20 to 50mg to patients and healthy volunteers[8,10,11 ,14] Peak plasma concentration

(~g/L)

<15-24

Time to achieve peak plasma concentration (h)

0.5-3.0

Apparent volume of distribution (Ukg)

3.7-5.0

Elimination half-life (h)

1.4-2.5 145-168 24.2-109.0 17.4-24.0

Clearance (Uh) AUC

(~g/L

• min)

Bioavailability (%)

Abbreviation: AUC = area under the plasma concentration-time curve.

© Adis International Limited, All rights reserved.

Results of animal studies after both intravenous and oral administration of tacrine revealed that the drug has extensive tissue distribution. In rats, high concentrations of the parent drug were found in the liver, kidney, adrenal gland and brain (cortex, hippocampus, thalamus and striatum), with uptake into the brain occurring rapidly.[19,20] C max values in the brains of rats were around 30-fold greater than those in plasma; however, cerebral extracellular tacrine concentrations were similar to those in plasmaPl] 2.2 Metabolism and Elimination

Tacrine is known to undergo rapid and extensive metabolism both in humans[22,23] and in experimental animals.l24 .25 ] In humans, 54% of an oral dose of [l4C]tacrine was excreted in the urine over 96 hours.l 22] Metabolites accounted for 67% of urinary recovery of radioactivity. The urinary metabolites are identified as 1-hydroxy-tacrine and other monohydroxy (2- and 4-), dihydroxy (5,6-, 7,8- and 1,3-) and glucuronide conjugates. Truman et aU23] also identified I-hydroxy-tacrine as a urinary metabolite in humans, with 4 other unidentified metabolites also present. In rats[24] and dogs,[25] the urine was again the primary route of excretion. 1-,2- and 4-hydroxy-tacrine were again identified as urinary metabolites. In humans, the Cmax of the I-hydroxy-metabolite, which has been shown to have some clinical activity,[26-29] was higher than that of tacrine. The tmax for the I-hydroxy-metabolite was short (0.5 to 1.5 hours after oral administration). The metabolic profile of tacrine has also been investigated in vitro using both rat and human tissue. The major hepatic microsomal metabolites were identified as 1-,2-,4- and 7-hydroxy-tacrine.l30,31] The extent of metabolism in human liver microsomes was significantly greater than that in rat liver microsomes. The formation of a hydroxylamine metabolite of tacrine in rat liver microsomes has been postulated;[32] however, this has not been supported by the results of other studies.[30,31] Both in vivo and in vitro studies of metabolism have indicated the involvement of the cytochrome Clin. Pharmacokinet. 28 (6) 1995

Madden et al.

452

: ceo I

7 -Hydroxy-tacrine

HO

§

OH

h

N

1-, 2- and 4-Hydroxy-tacrine

Phenol tacnnes

Dihydroxy tacrines Glucuronide conjugates

Dihydroxy tacrines

Fig. 1. Pathways of tacrine metabolism.

P450 family of enzymes in the metabolism of tacrine. One isozyme in particular, CYPIA2, has been identified as the predominant form in catalysing all the metabolic biotransformations of tacrine.[31,33-35] The metabolic profile of tacrine, derived from these studies, is shown in figure 1. The elimination half-life of tacrine varied from 1.4 to 2.5 hours after a single oral or intravenous dose[8,IO] and from 2.9 to 3.6 hours after multiple oral doses.[11.18] The apparent clearance of tacrine after intravenous doses of 15 and 30mg was high at 2.8 ± 0.8 and 2.4 ± 0.8 Umin (168 ± 48 and 144 ± 48 L/h), respectively. The elimination half-life of the I-hydroxy-metabolite appeared to be similar to that of the parent compound.[8,I2] Its formation and elimination are stereospecific, favouring the dextrorotary isomer,[36] whereas the metabolism of the I-hydroxy-metabolite to dihydroxy tacrines appears to be nonstereospecific. 2.3 Nonlinear Pharmacokinetics

Nonlinear pharmacokinetics of tacrine at low doses have been reported in a number of studies.[1l·14,18] Systemic availability after administra© Adis International Limited. All rights reserved.

tion of lOmg 4 times a day was approximately half of that achieved after administration of doses of 20 and 30mg 4 times daily; systemic availability ofthe 20 and 30mg dosage regimens being comparable,fll] Furthermore, Forsyth et al.[l8] reported that after increasing the single oral dose from 25 to 50mg, the resultant elimination half-life was increased from 1.5 to 2.1 hours. Cutler et al.[11] suggested that the lower bioavailability after administration of lOmg 4 times daily may reflect saturable hepatic uptake (resulting from saturation of firstpass metabolism) of tacrine, similar to that seen with propranoloI.l37]

3. Efficacy of Tacrine in Alzheimer's Disease Alzheimer's disease is the most common neurodegenerative disorder. It is characterised by a decline in memory, cognition and neurological function. Estimates suggest that 5 to 10% of people over 65 years of age living in the US and Europe[II,38] are affected by senile dementia, and half of these may have disease of the Alzheimer 's type. It is Clln. Phormacokinet. 28 (6) 1995

Tacrine Pharmacokinetics

predicated that up to 80% of those affected will die within 5 years of diagnosis.[39] In 1986, dramatic improvements in patients with Alzheimer's disease treated with tacrine were reported.[7] The results from this study caused an explosion of interest in the use of tacrine and led to many larger and better controlled clinical studies. Many of these studies have produced confusing and often conflicting results. For example, whilst the trials of Chatellier et aP40] and Gauthier et aP41] reported only slight improvements in only one outcome, the trial of Eagger et al.[42] reported significant improvements in 45% of patients who completed the study compared with only 11 % of the placebo group. Much of the controversy over the efficacy of tacrine demonstrated in these trials has been attributed to the design of the clinical trials. Drug dosage,[43] patient selection,[44] assessment of cognitive function[43,45] and washout periods between test and placebol46 ] have all been the subject of criticism. Recently, multicentre trials[47-49] have attempted to overcome many of the limitations of previous studies. In a 6-week, double-blind, placebocontrolled trial, patients were chosen on the basis of their responsiveness to tacrine in a preliminary crossover phase)47] Of the 632 patients who entered the trial, 215 showed improvement in the first phase and were enrolled into the second phase of the trial. These patients were randomly assigned to receive either placebo or the dose of tacrine found to be most effective in the first phase of the trial (i.e. either 10 or 20mg 4 times daily). At the end of the 6-week trial, patients receiving tacrine showed a significant improvement in the Alzheimer's Disease Assessment Scale (ADAS), indicative of a smaller decline in cognitive function compared with that in the placebo group. None of the other outcome measures showed significant differences between the groups. It was therefore concluded that in this short term study tacrine caused a reduction in the decline of cognitive function. However, this reduction was not large enough to be de© Adis International limited. All rights reserved.

453

tected by the physician's global assessments of the patients. Farlow et aP48] carried out a 12-week, doubleblind, placebo-controlled, parallel group study. Patients were at least 50 years old with mild to moderate Alzheimer's disease. In contrast to the study of Davis et al.,l47] no preliminary crossover phase was employed. Data for the complete 12-week study were available from 273 patients. Significant dose-related improvements were seen on ADAS, clinician-rated Clinical Global Impression of Change (CGIC), or the caregiver-rated CGIC. Among patients receiving tacrine 80 mg/day, 51 % achieved a 4 point or greater improvement in the cognitive component of the ADAS. These authors concluded that their results confirmed the efficacy and tolerability of tacrine in some patients with Alzheimer's disease.[48] The efficacy of high-dose tacrine (160 mg/day) has recently been examined by Knapp et al)49] Study design was similar to that of Farlow et aP48] The trial was over 30 weeks and the tacrine dosage was titrated up to a maximum of 160 mg/day. Data from 263 patients were evaluable at 30 weeks. Statistically significant, dose-related improvements in objective performance-based tests, clinician- and caregiver-rated global evaluations and measures of quality oflife were demonstrated. Despite the large number of patient withdrawals, particularly at the highest dosage, supplemented analyses supported the investigators' conclusion that this did not bias the overall results.[49] Therefore, despite many improvements in the design of clinical studies to determine the efficacy of tacrine in Alzheimer's disease, there is still considerable debate on the effectiveness of the drug in patient populations. [50-52] However, most authors do agree that there is a definite population of patients with Alzheimer's disease who would benefit from tacrine therapy. Interindividual variations in pharmacokinetics may, in part, explain why only small effects are seen with tacrine therapy in some patients. Indeed, Eagger and Levy[53] have reported that improvements in the clinical state of patients receiving tacrine were correlated with Clin. Pharmacokinet. 28 (6) 1995

454

blood concentrations of the drug, suggesting that the potential benefit of tacrine may only be properly evaluated when adequate blood concentrations are attained.

4. Tolerability The development of adverse effects during tacrine therapy are well documented. Ahlin et aUlO] have suggested that the bioavailability of tacrine and the incidence of dose-related adverse effects (i.e. cholinergic effects) are well correlated. Furthermore, other investigators have indicated that serum concentrations of tacrine may be useful in predicting these adverse effects.u 6] Both symptomatic and asymptomatic adverse reactions have been described.[l6,42,48,54] In early clinical trials, withdrawals were high as the result of development of elevations in serum aminotransferase levels. Indeed, the first multicentre clinical trial was halted after only 2 months when 7 of the 50 enrolled patients developed unexpected elevations in serum alanine aminotransferase (ALT) levels)55] Elevations of ALT levels, and the potential for the development of clinically significant hepatotoxicity continue to be the major safety concern associated with tacrine therapy. The hepatotoxic effects of tacrine in patients with Alzheimer's disease were recently reviewed.[54] The review covered data from 2446 patients who had taken part in multicentre clinical trials in the US, France and Canada. The incidence of elevations in ALT levels was high; 49% of patients had ALT levels elevated above the upper limit of normal (40 U/L) on at least 1 occasion. ALT levels of 3-fold higher than the upper limit of normal occurred in 25% of patients, and in 2% of patients ALT levels were more than 20 times above the upper limit of normal. It took a mean of 50 days for ALT to increase above levels 3-fold greater than the upper limit of normal, and 90% of all ALT levels that were greater than 3 times the upper limit of normal occurred within the first 12 weeks of therapy. Discontinuation of therapy completely reversed elevations in ALT levels. Interestingly, of the 145 patients who had ALT levels greater than 3 © Adls International Limited. All rights reserved.

Madden et al.

times the upper limit of normal, 88% were able to resume long term therapy with no adverse effect. Careful monitoring for elevations in the serum level of ALT should therefore reduce the potential for serious hepatic insult. The mechanism of the hepatic injury, evidenced by the increase in ALT levels, caused by tacrine is unclear. Rapid and extensive metabolism of the drug[22.23] suggests that the causative agent is unlikely to be tacrine per se. Furthermore, rechallenge data[54] suggest that an immunological mechanism is unlikely. There appears to be no known relationship between plasma concentrations of tacrine and the development of elevated transaminase levels. Perhaps the best indications of the mechanism of toxicity have come from in vitro studies of metabolism. We[30,31,34] and others[56] have demonstrated the potential for tacrine to undergo enzyme mediated bioactivation to both protein-reactive and cytotoxic metabolites in hepatocytes and in hepatic microsomes from humans and rats. Furthermore, the enzyme responsible for this bioactivation, CYPIA2, is the same enzyme responsible for the formation of the other, nontoxic, metabolites of tacrine. If these reactive metabolites that have been demonstrated in vitro are formed from tacrine in vivo, they have the potential to interact with essential macromolecules and proteins within the liver to initiate the hepatic damage that is evidenced by elevations in ALT. [57] Autonomic adverse reactions, attributable to the cholinergic effects of the drug, are also common in patients receiving tacrine, and occur in 32 to 80% of patients receiving treatment)40,48] These are, however, generally mild and are reversible on reduction of the dosage. The most common adverse events in patients receiving tacrine were: nausea, vomiting, diarrhoea, dyspepsia, myalgia, anorexia, rhinitis, rash, ataxia, flatulence, body weight loss, vasodilation, tremor, sweating and beIching.[48,58]

5. Drug Interactions To date little information is available on the occurrence of drug interactions between tacrine and other therapeutic agents. The data that are available Clin. Pharmacokinet. 28 (6) 1995

455

Tacrine Pharmacokinetics

indicate the potential for interactions with other drugs that are known to interact with the form of cytochrome P450 (i.e. CYPIA2) responsible for the metabolism of tacrine. Theophylline, for example, is a well characterised substrate for this enzyme.l59] In vivo theophylline blood concentrations have been shown to be elevated in patients receiving concomitant tacrine therapy.[60] The H2receptor antagonist cimetidine is known to inhibit CYPIA2 activity both in vitro and in vivo. We have previously demonstrated[34] inhibition of tacrine metabolism by cimetidine in an in vitro test system. In vivo, de Vries et aU 6l ] have shown increased plasma concentrations of tacrine in patients also receiving cimetidine, this may also be accounted for by an inhibition of CYPIA2-mediated metabolism of tacrine by cimetidine. Constituents of cigarette smoke are known to be inducers of CYPIA2.[62,63] Smoking may, therefore, potentially increase the rate of tacrine metabolism, thus lowering plasma concentrations. Indeed, in a preliminary study,[64] smoking was found to decrease the plasma concentrations of tacrine. Therefore, the effects of smoking on the pharmacokinetics, efficacy and toxicity of tacrine merit further investigation.

6. Conclusions Tacrine is the first drug to be approved for the treatment of Alzheimer's disease. Despite considerable debate over its effectiveness in all patients with Alzheimer's disease, there appears to be a definite population who benefit from tacrine therapy. The pharmacokinetics of tacrine are characterised by high and rapid absorption, low oral bioavailability, wide tissue distribution, rapid and extensive hepatic metabolism and rapid elimination of the drug. Large interindividual variation in pharmacokinetic profiles are seen in both patient and control groups. This may in part explain the lack of efficacy seen in some patients. Adverse effects to therapy are the major limiting factors in the use of tacrine. While symptomatic (cholinergic) effects are clearly related to dose and/or plasma concentrations of tacrine, asymp© Adis Internat ional Limited. All rights reserved.

tomatic effects (elevation of serum transaminase levels) may be dependent upon the generation of a toxic species from the parent compound.

Acknowledgements We gratefully acknowledge the financial support of Parke-Davis Pharmaceutical Research (SM), the Medical Research Council (VS) and the Wellcome Trust (BKP).

References 1. Shaw FH, Bentley GA. Pharmacology of morphine, with special reference to its antagonism by 9-aminoacridine and other related compounds. Med J Aust 1949; II: 868-74 2. Stone V, Moon W, Shaw FH. Treatment of intractable pain with morphine and THA. BMJ 1961 ; 1: 471-3 3. Jones CR, Davis M. Replacement drug for edrophonium. Med J Aust 1975; 2: 650 4. Summers WK, Kaufman KR, Altman F, et al. THA: a review of the literature and its use in the treatment of five overdose patients. Clin Toxicol 1980; 16: 269-81 5. McCaul K, Robinson GD. Suxamethonium extension by tetrahydroaminoacrine. Br J Anaesth 1962; 34: 536-42 6. Gershon S. Blocking effect of tetrahydroaminoacrin on a new psychotomimetic drug. Lancet 1960; 186: 1072-3 7. Summers WK, Majovski LV, Marsh GM, et al. Oral tetrahydroaminoacridine in long term treatment of senile dementia, Alzheimer type. N Engl J Med 1986; 315: 1241-5 8. Hartvig P, Askmark H, Aquilonius SM, et al. Clinical pharmacokinetics of intravenous and oral 9-amino-I,2,3,4-tetrahydro acridine, tacrine. Eur J Clin Pharmacol 1990; 38: 259-63 9. Fredj G, Dietlin F, Jasmin C, et al. Open trial of tacrine therapy in 70 HIV infected patients. IntJ Clin Pharmacol TherToxicol 1992; 30: 313-6 10. Ahlin A, Adem A, Jonthe T, et al. Pharmacokinetics of tetrahydroaminoacridine: relations to clinical and biochemical effects in Alzheimer's patients. Int Clin Psychopharmacol 1992; 7: 29-36 II. Cutler NR, Sedman AJ, Prior P, et al. Steady-state pharmacokinetics of tacrine in patients with Alzheimer's disease. Psychopharm Bull 1990; 26: 231-4 12. Ekman L, Lindstrom B, Roxin P. Determination of tacrine and its I-hydroxy metabolite in plasma using column liquid chromatography with ultraviolet detection. J Chromatogr 1989; 494: 397-402 13. Forsyth DR, Ford JM, Truman CA, et al. Determination oftacrine hydrochloride in human serum by chloroform extraction, reversed-phase high-performance liquid chromatography and fluorometric detection. J Chromatogr 1988; 433: 352-8 14. Selen A, Bulogh L, Siedlik P, et al. Pharmacokinetics of tacrine in healthy subjects. Pharm Res 1988; 5: S218 15. Ahlin A, Nyback H, Jonthe T, et al. Tetrahydroaminoacridine in Alzheimer's dementia clinical and biochemical results of a double-blind crossover trial. Hum Psycopharm 1991; 6: 109-18 16. Ford JM, Truman CA, Wilcock GK, et al. Serum concentrations of tacrine hydrochloride predict its adverse effects in Alzheimer's disease. Clin Pharmacol Ther 1993; 53: 691-5 17. Nyback H, Nyman H, Ohman G, et al. Preliminary experiences and results with THA for the amelioration of symptoms of Alzheimer's disease. In: Giacobini E, Becker R, editors. Cur-

Clin. Pharmacokinet. 28 (6) 1995

456

rent research in Alzheimer therapy. New York: Taylor Francis, 1988: 231-6 18. Forsyth DR, Wilcock GK, Truman CA, et al. Pharmacokinetics of tacrine hydrochloride in Alzheimer's disease. Clin Pharmacol Ther 1989; 46: 634-41 19. McNally W, Roth M, Young R, et al. Quantitative whole-body autoradiographic determination of tacrine tissue distribution in rats following intravenous or oral dose. Pharm Res 1989; 6: 924-36 20. Telting-Diaz M, Lunte CE. Distribution of tacrine across the blood-brain barrier in awake, freely moving rats using in vivo microdialysis sampling. Pharm Res 1993; 10: 44-8 21. Baldwin HA, de Souza RJ, Sarna GS, et al. Measurements of tacrine and monoamines in brain by in vivo microdialysis argue against release of monoamines by tacrine at therapeutic doses. Br J Pharmacol1991; 103 : 1946-50 22. Pool WF, Bjorge SM, Chang T, et al. Metabolic disposition of the cognition activator tacrine in man: identification of phenol glucuronide metabolites in urine. ISSX Proceedings Fourth North American ISSX Meeting 2; 1992 Nov: Bal Harbour, Florida. 1992: 164 23. Truman CA, Ford JM, Roberts CJe. Comparison of the chromatographic characteristics of metabolites of tacrine hydrochloride in human serum and urine with those of in vitro metabolic products from hepatic microsomes. Biochem Pharmaco11991; 42: 956-9 24. Hsu RS, Schutske GM, Dileo EM, et al. Identification of the urinary metabolites of tacrine in the rat. Drug Metab Dispos 1990; 18: 779-83 25. Pool WF, Bjorge SM, ReiIIy MD, et al. Metabolic disposition of the cognition activator tacrine in dog: identification of dihydroxy metabolites including a dihydrodiol. ISSX Proceedings Fourth North American ISSX Meeting 2; 1992 Nov: Bal Harbour, Florida: 163 26. Goa KL, Fitton A. Velnacrine in Alzheimers disease: an initial appraisal of its clinical potential. CNS Drugs 1994; 1: 232-40 27. Puri SK, Hsu R, Ho I, et al. Single-dose safety, tolerance and pharmacokinetics of HP 029 in elderly men: a potent Alzheimer agent. Curr Ther Res 1988; 44: 766-80 28. Murphy MF, Hardiman ST, Nash RJ, et al. Evaluation of HP029 (velnacrine maleate) in Alzheimer's disease. Ann NY Acad Sci 1991; 640: 253-62 29. Siegfried KR. Pharmacodynamic and early clinical studies with velnacrine. Acta Neurol Scand Suppl 1993; 149: 26-8 30. Madden S, WoolfTW, Pool WF, et al. An investigation into the formation of stable, protein-reactive and cytotoxic metabolites from tacrine in vitro. Studies with human and rat liver microsomes. Biochem Pharmacol1993; 46: 13-20 31. Woolf TF, Pool WF, Bjorge SM, et al. Bioactivation and irreversible binding of the cognition activator tacrine using human and rat liver microsomal preparations. Species differences. Drug Metab Dispos 1993; 21: 874-82 32. Hendrickson HP, Scott DO, Lunte CEo Identification of a 9-hydroxylamine 1,2,3,4-tetrahydroacridine as a hepatic microsomal metabolite of tacrine by high-performance liquid chromatography and electrochemistry. J Chromatogr 1989; 487: 401-8 33. Pool WF, Bjorge SM, Chang T, et al. Effect of 3-methyl cholanthrene induction on the disposition of the cognition activator tacrine in the rat. ISSX Proceedings Fourth North American ISSX Meeting 2; 1992 Nov: Bal Harbour, Florida: 165 34. Spaldin V, Madden S, Pool WF, et al. The effect of enzyme inhibition on the metabolism and activation of tacrine by

© Adis International Limited. All rights reserved.

Madden et al.

human liver microsomes. Br J Clin Pharmacol 1994; 38: 15-22 35. Woolf TF, Pool WF, Kukan M, et al. Characterization of tacrine metabolism and bioactivation using heterologous expression systems and inhibition studies: evidence for CYPIA2 involvement. Fifth North American ISSX Meeting; 1993 Oct 17-21; Tuscon, Arizona 36. Hooper WD, Pool WF, WoolfTF, et al. Stereoselective hydroxylation of tacrine in rats and humans. Drug Metab Dispos 1994; 22: 719-24 37. Evans GH, Shand DG. Disposition of propranolol V. Drug accumulation and steady-state concentrations during chronic oral administration. Clin Pharmacol Ther 1973; 14: 487-93 38. Hofman A, Rocca WA, Brayne C, et al. The prevalence of dementia in Europe: a collaborative study of 1980-1990 findings. IntJ Epidemio1 1991; 20: 736-48 39. Christie AB. Alzheimer 's disease: the prognosis. In: Pitt B, editor. Dementia. Edinburgh: Churchill Livingstone, 1987: 197-208 40. Chatellier G, Lancomblez L, on behalf of Group Francais d'Etude de la tetrahydroamino acridine. Tacrine (tetrahydroaminoacridine; THA) and lecithin in senile dementia of the Alzheimer type: a multicenter trial. BMJ 1990; 300: 495-9 41. Gauthier S, Bouchard R, Lamontayne A, et al. Tetrahydroaminoacrine-Iecithin combination treatment in patients with intermediate stage Alzheimer's disease: results of a Canadian double-blind, crossover, multicenter study. N Engl J Med 1990; 322: 1272-6 42. Eagger SA, Levy R, Sahukian RJ. Tacrine in Alzheimer 's disease. Lancet 1991;337: 989-92 43. Levy R. Tacrine and Alzheimer's disease. BMJ 1990; 300: 939-40 44. Katona CLE, O'Brien e. Tetrahydroaminoacridine and Alzheimer's disease. Lancet 1987; I: 444 45. Jones RW. Tacrine in Alzheimer's disease. Lancet 1991; 337: 1475-6 46. Wilcock GK. Tacrine and lecithin in Alzheimer's disease [letter]. BMJ 1990; 300: 939 47. Davis KL, ThaI LJ, Garnzu ER, et al. A double-blind, placebocontrolled, multi-center study of tacrine for Alzheimer's disease. N Engl J Med 1992; 327: 1253-9 48. Farlow M, Gracon SI, Hershey LA, et aI. A controlled trial of tacrine in Alzheimer's disease. JAMA 1992; 268: 2523-9 49. Knapp MJ, Knupmam DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA 1994; 271: 985-91 50. Small Ow. Tacrine for treating Alzheimer's disease. JAMA 1992; 268: 2564-5 51. Growdon JH. Treatment for Alzheimer's disease? N Engl J Med 1992; 327: 1306-8 52. Winker M. Tacrine for Alzheimer's disease: which patient, what dose? JAMA 1994; 271: 1023-4 53. Eagger SA, Levy R. Serum levels of tacrine in relation to clinical response in Alzheimer's disease. Int J Oeriatr Psychiatry 1992; 7: 115-9 54. Watkins P, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA 1994; 271: 992-8 55. Marx Je. Alzheimer's drug trial put on hold. Science 1987; 238: 1041-2 56. Dogterom P, Nagelkerke JF, Mulder OJ. Hepatotoxicity of tetrahydroaminoacridine in isolated rat hepatocytes: effect of glutathione and vitamin E. Biochem Pharmacol 1988; 37: 2311-3

Clin. Pharmacokinet. 28 (6) 1995

Tacrine Pharmacokinetics

57. Park BK, Madden S, Spaldin V, et al. Tacrine transaminitis: potential mechanisms. Alz Dis Assoc Disord 1994; 8 Suppl. 2: S39-S49 58. Wagstaff AJ, McTavish D. Tacrine: a review of its phannacodynamic and pharmacokinetic properties and therapeutic potential in Alzheimer's disease. Drugs Aging 1994; 4: 510-40 59. Robson RA, Miners JO, Matthews AP, et al. Characterisation of theophylline metabolism by human liver microsomes inhibition and immunochemical studies. Biochem Pharmacol1987; 37: 1651-9 60. de Vries TM, Siedlick P, Smithers lA, et al. Effect of multipledose tacrine administration on single-dose pharmacokinetics of digoxin, diazepam and theophylline [abstract]. Pharm Res 1993; 10: S334 61. de Vries TM, O'Connor-Semmes RL, Koup JR, et al. Effect of cimetidine and low-dose quinidine on tacrine pharmacokinetics in humans [abstract]. Pharm Res 1993; 10: S377

© Adis International limited. All rights reserved.

457

62. Crowley JJ, Cusack BJ, Jue SO, et al. Cigarette smoking and theophylline metabolism: effects of phenytoin. Clin Pharmacol Ther 1987; 42: 334-40 63. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol 1992; 22: 23-43 64. Welty D, Pool WF, Woolf TF, et al. The effect of smoking on the pharmacokinetics and metabolism of cognex in healthy volunteers [abstract]. Pharm Res 1993; 10: 8143

Correspondence and reprints: Dr Stephen Madden, Department of Pharmacology and Therapeutics, University of Liverpool, PO Box 147, Ashton Street, Liverpool L69 3BX, England.

Clin. Pharmacokinet. 28 (6) 1995