L

Clinical Pharmacokinetics of Propranolol

spuriously low plasma propranolol concentrations (Cotham and Shand, 1975). It was suggested that a chemical present in the rubber stopper leached out and displaced the drug from its binding sites. The free drug was then taken up by red cells to form a new equilibrium with less propranolol present in plasma, although the whole blood propranolol concentration was unaltered. A plasticiser, tris (2-butoxyethyO phosphate (TBEP) had been identified in plasma collected in the same type of tube (Misson and Dickson, 1974) and it was subsequently shown that this compound could displace several basic drugs from their binding sites on (XI-acid glycoproteins; including alprenolol, imipramine, chlorimipramine and nortriptyline (Horga et aI., 1977). Spuriously low plasma concentrations have also resulted from the use of 'Vacutainer' tubes with pethidine (meperidine; Wilkinson and Schenker, 1976), quinidine (Fremstad, 1976) and lignocaine (lidocaine; Stargel et aI., 1979). Thus, while this phenomenon is not invariable, it does extend to drugs other than propranolol. Unfortunately, it is not always possible to judge the impact of this problem on the early literature as collection methods were seldom reported. We do know that vacutainers have not been used by British workers (such as the groups of Dollery and George), nor have the publications of Shand or Walle been influenced by this, as all glass systems and separate venipuncture were used. It has also been shown that a piastic syringe did not iower piasma propranoloi concentration or increase the red cell/plasma concentration ratio compared with a glass syringe (Cotham and Shand, 1975). 1.1.2 Indwelling Cannulae

Cotham and Shand (J 975) reported spuriously low levels of propranolol in a subject due to the use of a 'Butterfly' needle, but could not reproduce the phenomenon subsequently. Recently, Wood et al. (J 979) have reported that the use of heparin locks may alter plasma propranolol binding. They found the administration of as little as 50 units of heparin increased the free drug fraction from an average of

74

9.9 % to 12.6 %. As heparin has no direct effect on propranolol binding it was suggested the free fatty acid release in vivo could displace propranolol from its plasma binding sites. Multiple blood samples are often taken through indwelling cannulae which are flushed with heparinised saline to prevent clot formation. Even the small concentrations of heparin used for this purpose could result in spuriously low plasma propranolol concentrations, due to a redistribution phenomenon akin to that seen with collection tubes. It is therefore important to test all collection procedures periodically and if a suitable indwelling cannula is used, to avoid the use of heparin.

1.2 Assay Methods The earliest and most commonly used method for propranolol estimation has been the fluorometric procedure of Black and co-workers (Black et aI., 1965), as modified by Shand and colleagues (Shand et aI., 1970). Other modifications of the method have also been published (Ambler et aI., 1974; Offerhaus and Van der Vecht, 1976; Kraml and Robinson, -1978). The recovery and reproducibility of the Shand modification are good (Shand et ai., 1970; Kraml and Robinson, 1978), as is the specificity of the method for propranolol rather than its metabolites. It has been shown that only N-desisopropyl propranolol has significant fluorescence under the assay conditions, but it is probably present in much too low concentrations in biological samples to interfere with the assay (Kraml and Robinson, 1978; Black et ai., 1965; Walle and Gaffney, 1972). The major problem has been the high and variable background fluorescence which may even vary from day to day in the same subject (Chidsey et at., 1975). This fluorescence may be due to the presence of other drugs and their metabolites, contaminants in the assay, or endogenous compounds. Recently, Wood et al. (1978a) have compared the fluorometric assay with a high performance liquid chromatographic (HPLC) method (vide infra) and found a good correlation, provided the subject's own blank plasma was available for fluorometry.

75

Clinical Pharmacokinetics of Propranolol

Correspondence was poor, however, with routine clinical samples. As a result of these problems more sensitive gas chromatographic procedures were developed (DiSalle et aI., 1973; Walle, 1974), but these are time consuming and involve derivatisation steps. The most specific method of propranolol estimation involves gas chromatography and mass fragmentography of the trifluoracetyl derivative of propranolol using selective ion monitoring (Walle et aI., 1975). This method can detect propranolol at a concentration of I ng/ ml plasma and has the added advantage that it also measures the active metabolite, 4-hydroxypropranolol. It is time consuming however, and also requires access to a mass spectrometer. Several workers have therefore developed sensitive high performance liquid chromatographic assays for propranolol using fluorescence detection (Mason et aI., 1977; Mackichan et aI., 1978; Nation et aI., 1978; Simon and Babich-Armstrong, 1979; Wood et aI., 1978a). A sensitive and stereospecific radioimmunoassay for I-propranolol and d-propranolol l has also been developed, although its use has been limited by availability of antisera (Kawashima et aI., 1976). Of the assay methods available, HPLC combined with variable wave length fluorometric detection offers the advantage of a chromatographic separation without derivatisation. The HPLC assay of Wood et al. (I 978a) has shown good correspondence with the Shand modification (when the subject's blank plasma was used to determine the standard curve) and with a radioimmunoassay developed by Butler. The Simon HPLC assay compares well with GC/MS (Walle, Simon and Ibbott, personal communication). The validity ofthe HPLC assay versus GC/MS is important in explaining differences between the findings

I Propranolol as available for clinical use is a racemic mixture consisting of equal parts of the d- and I-isomers. The d-isomer does not possess ~-adrenoceptor blocking activity, although both the d- and I-isomers show other nonspecific activity, including membrane stabilising action ('quinidine-like' or 'local anaesthetic' effect>.

shown in figure I and those of Walle et al. (I 978a) regarding individual variability (see section 3) but at present we would conclude that the basic pattern of propranolol kinetics established over the past decade has not been materially distorted by analytic or blood collection methods.

2. Fundamental Pharmacokinelic Properties 2.1 Absorption Propranolol is virtually completely absorbed after oral administration (Paterson et aI., 1970). Peak plasma concentrations of propranolol are seen at approximately 2 hours (range I to 4 hours) in fasting patients (Paterson et aI., 1970; Shand and Rangno, 1972; Lowenthal et aI., 1974; Parsons et aI., 1976; Castled en et aI., 1975, 1978). Adininistration of food does not significantly change the time to peak levels in healthy individuals given a single tablet of propranolol with a standardised meal, though systemic availability was increased (Melander et aI., 1977). There appears to be no relationship between the halflife of gastric emptying and the time of attainment of peak plasma propranolol concentration (Castleden et aI., 1978).

2.2 Metabolism Early work in healthy young volunteers established that propranolol was eliminated almost entirely by metabolism; only I to 4 % of a radiolabelled dose being recovered as unchanged drug in the urine and faeces (Paterson et aI., 1970). Four primary pathways of metabolism of propranolol have been described - O-dealkylation, side chain oxidation, glucuronic acid conjugation and ring oxidation. The ring hydroxylated metabolite, 4-hydroxypropranolol, was observed in plasma only after oral administration and was observed to have some ~­ adrenoceptor blocking activity (Paterson et aI., 1970; Fitzgerald and O'Donnell, 1971). Since then, other

Clinical Pharmacokinetics of Propranolol

76

ring hydroxylated metabolites have been identified in human plasma and urine, mainly as glucuronic acid and/ or sulphate conjugates. Alteration in the ring system without changes in the side chain would be expected to produce active metabolites but the biological significance of these recently described products is still unclear (Walle et ai., 1978b). O-Dealkylation and side chain oxidation lead to a variety of metabolites including naphthoxylactic acid, which accounts for 20 % of single oral doses and 40 % of single intravenous doses of propranolol (Paterson et ai., 1970). Glucuronidation of propranolol, 4-hydroxypropran0101 and several other metabolites also oCcurs (Walle et ai., 1976, 1977). Propranolol-O-glucuronide accounts for 2.5 to 25 % of total excretion of continued

400

30

E

'-

OJ

.s

200

(,)

c: 0

(,)

~c:

100

ec. '" E a::'"

0

~

C.

CI)

2

,

B

Time (hours)

Fig. 1. Individual variation in plasma propranolol concentration in hospitalised. drug free normal volunteers aged 21 to 13 years receiving BOmg every B hours. Concentrations were determined by HPLC after the administration of the ninth dose in the fasting state (Wood. Vestal and Shand. unpublished).

oral doses of propranolol ranging from 40 to per day (Walle et ai., 1977).

~20mg

2.3 Distribution Propranolol is widely distributed through body tissues, the apparent volume of distribution derived from the ~ portion of the concentration time curve (Vd~) is approximately 200 litres, indicating drug accumulation in some tissues (Shand et ai., 1970). This is supported by experimental data in animals which indicates high concentrations of propranolol in lung, liver, kidney, brain and heart after oral and intravenous administration of propranolol (Hayes and Cooper, 1971; Myers et ai., 1975). Propranolol is highly bound (85 to 96 %) to proteins in plasma in man (Evans et ai., 1973a; Borga et ai., 1977; Sager et ai., 1978). Since binding to human serum albumin (5g/ 100mO is only 62 %, other proteins are also important in determining the degree of binding (Evans et ai., 1973a). Propranolol is bound to lipoproteins independently of propranolol concentration, and also to IX I acid glycoprotein and this protein is responsible for 75 % of binding of propranolol in plasma at therapeutic propranolol concentrations (Sager et ai., 1978). The degree of plasma binding is one determinant of the distribution of propranolol into tissues, including the red blood ceUs. Thus, Vd~ increased as plasma binding falls over the normal range (Evans et ai., 1973a). When volume of distribution is calculated in terms of free drug concentration, this. was less variable than Vd~ for total drug, implying a relative constancy of tissue uptake. The same is true of the red cells which were shown to partition about 5 : I with free drug in plasma (Jellett and Shand, 1973). The blood/plasma concentration ratio varies from about 0.7 to 0.85, depending on plasma binding and haematocrit (Evans and Shand, 1973b; Vervloet et ai., 1978; Bianchetti et ai., 1976). It merits re-emphasis that drug clearances must be computed in terms of whole blood in order to have biological meaning (Rowland, 1972) so that knowledge of the blood/ plasma concentration ratio is

Clinical Pharmacokinetics of Propranolol

important to a proper kinetic evaluation of plasma values.

2.4 Elimination After intravenous administration, drug concentrations decline biexponentially and whole blood clearance is very high at about I L/ min (Shand et al., 1970). Recently, Pessayre et al. (J 978) have shown that the elimination of the d-isomer is essentially confined to the liver. Recognising that ~-adrenoceptor blockade lowers liver blood flow by some 20 to 30 % (Nies et aI., 1973), this clearance value closely approaches that of hepatic blood flow, implying a very high extraction efficiency. Indeed, Weiss et al. (J 978) have suggested that intravenous d-propranolol, which does not produce ~-blockade, might be used to assess liver blood flow. Because of the efficient clearance of propranolol, it, has a relatively short half-life (hours) after intravenous administration in young subjects (Shand et al., 1970).

2.5 Non-linear Kinetics The kinetics of propranolol are more complex after oral administration despite its complete absorption across the alimentary tract (Paterson et al., 1970). Not only does the avid hepatic extraction dictate low systemic availability because of presystemic (,first-pass') elimination, but this process is also dose dependent. Shand and Rangno (1972) first noted that, in contrast to the intravenous route, the relationship between the area under the plasma concentration/time curve (AUe) after single oral doses was not proportional to dose. With a 20mg dose, only trace amounts of propranolol were detected but larger doses became progressively more available. Over the range of 40 to 160mg there was a linear relationship of AUe with dose, back extrapolation of which yielded an apparent threshold dose of 30mg. These findings have been both misinterpreted and challenged. It was never suggested that presystemic

77

extraction was complete at ·low doses, only that availability was relatively less than with larger doses. Thus, the fact that Davies et al. (J 978) could detect the effect of a single 5mg oral dose is not surprising in view of the drug's potency. Nor can one comment on a non-linear phenomenon by investigating only a single dose. Dose dependency was challenged by the studies of Gomeni et al. (J 977) who found a linear relationship between AVe and oral dose over the range of 10 to 40mg. However, the average half-life of propranolol was calculated to be as long as 9.4 hours at I Omg but 3.5 hours after larger doses in the same subjects. Since the limit of sensitivity (about 2ng/ mO of the assay method used was close to the values used to determine the half lives at 10mg, it is probable that the AVe at the lower doses was thus overestimated. Vsing a more sensitive assay method half-lives ranging from 2.5 to 5.6 hours were noted in 3 healthy volunteers given 10mg propranolol orally, and the mean AVe was almost half of the mean AVe observed by Gomeni and co-workers (Mackichan et al., 1978). Moreover, these workers confirmed non-linearity, though the apparent threshold was smaller (Jusko, personal communication). Non-linear systemic availability has also been confirmed after intraportal administration in rats (Suzuki et al., 1972, 1974) and in perfused livers (Evans et a\., 1973b). It has been postulated that non-linearity is due to saturation of a high affinity uptake or binding site in the liver as a result of the high portal venous drug concentrations after oral administration. There is evidence in isolated perfused rat livers for 2 reversible physical binding processes, one with high affinity, but low capacity and the other with high capacity but low affinity (Evans et al., 1973b). Autoradiography of rat livers indicated high concentrations of propranolol in the periportal zones of the liver lobule (Anderson et al., 1978). The high affinity process appeared to have a capacity of approximately 500~g of propranolol per gram weight of liver and was flow limited (Shand et a\., 1973). The lower affinity process was associated with metabolism of propranolol; was temperature, oxygen and flow dependent, and was affected by

Clinical Pharmacokinetics of Propranolol

several other drugs (Anderson et aI., 1978). Another explanation might be that saturation of a metabolic pathway occurs, which would be consistent with the fact that the active metabolite, 4-hydroxypropranolol, is produced only after oral administration and not after conventional intravenous doses (Paterson et aI., 1970). It is altogether possible that saturation of uptake or binding could be associated with a change in metabolic pattern. Propranolol also accumulates during continued oral administration to a greater extent than predicted from its half-life and continued saturation of high affmity extraction through the dosage interval has been suggested (Evans and Shand, 1973a). Such accumulation has recently been confirmed and shown to be associated with a decrease in presystemic extraction from 78 % after the first dose to 66 % at steadystate following 80mg 8-hourly (Wood et aI., I 978a). It was originally suggested on the basis of plasma levels at the end of the dose, that the systemic availability would be linear at steady-state; at least with small doses (Evans and Shand, 1973a). This has been refuted by a most thorough study by Walle et aI. (J 978a) who clearly demonstrated an apparent threshold of about 100mg daily during steady-state. Furthermore, this group has also shown that the proportion of 4-hydroxypropranolol to parent drug declines from a value of unity at 160mg daily to 0.1 at higher doses, again implying saturable metabolism (Walle et aI., 1977). In summary, the evidence for non-linear kinetics of propranolol is overwhelming, but differs from classic Michaelis-Menten kinetics in that once the apparent threshold is exceeded, there seems to be a good linear relationship between dose and plasma concentrations. This poses methodological problems in investigating the factors responsible for variable plasma levels at steady-state because the orally administered drug is clearly handled differently from single intravenous doses. This problem has recently been overcome by giving )H-propranolol intravenously during continued oral administration of the native drug. By measuring lH and native drug simultaneously by fluorometry (Kornhauser et aI.,

78

Table I. Some parameters of propranolol disposition at

steady-state'

-------------------Abbreviation

Average value

Systemic blood clearance of total drug

Cis

0.9L/min

Apparent oral blood clearance of total drug

Clo

2.71L/min

Intrinsic blood clearance of total drug

Cli

2.71L/min

Intrinsic blood clearance of unbound drug

Cli (free)

32.18L/min

Fractional systemic availability

F

0.36

Half -life of elimination from blood

t1/2~

3.9h

Apparent volume of distribution

Vd~

295l

Apparent liver blood flow

Q

1.43L/min

Hepatic extraction ratio

E

0.64

Fraction of drug unbound in blood

fS

0.086

Fraction of drug unbound in plasma

fp

0.067

Siood to plasma concentration ratio

SIP

0.78

Red cell to plasma concentration ratio

RIP

0.51

1 Measured in young adult subjects (mean age 33 years. mean weight 75kg) at steady-state (80mg propranolol tid) [Kornhauser et al.. 1978].

1978) or HPLC (Wood et aI., I 978a), the kinetics of intravenous and/or oral drug can be measured simultaneously at steady-state. This is an extremely powerful technique, that in the case of propranolol can also be used to measure liver blood flow (Wilkinson and Shand, 1975; Kornhauser et aI., 1978). A verage values for some disposition properties of propranolol in adults are shown in table I.

Clinical Pharmacokinetics of Propranolol

3. Individual Variability and its Causes 3. 1 Intravenous Administration Following the formal kinetic analyses of Gibaldi et al. (I 971) and Rowland (I 972), it became abundantly

clear that the disposition of highly extracted drugs, like propranolol, would be very dependent on the route of administration. Since the pioneer work of Brauer (I 963) it has been repeatedly demonstrated that the hepatic clearance of highly extracted drugs is dependent on liver blood flow. Recognising that liver blood flow varies only about 2-fold in normals, the similar variability in the intravenous clearance of propranolol (Shand et ai., 1970) and in steady-state plasma concentration during an infusion (Woosley and Shand, 1978) is not surprising. Reduced clearance of intravenously administered drug in the elderly (Castleden and George, 1979) is also consistent with the known reduction in liver blood flow in the elderly (Sherlock et ai., 1950). The extraction process is so efficient after intravenous administration that drug can be functionally stripped from its binding sites, so that altering plasma binding over the normal range has no effect on drug clearance (Evans et aJ., 1973a). Thus, differences in drug binding in blood will result in changes in free drug without a change in total drug concentration. Plasma binding does, however, still affect the apparent volume of distribution, and thereby drug halflife. As a result, the greater the plasma binding, the smaller is the distribution volume and the shorter the half-life. Because binding in blood did not affect clearance, this type of elimination was termed nonrestrictive (Wilkinson and Shand, 1975), in which case binding in blood can be visualised as a transport system bringing drug from the tissues to the liver which can extract both bound and free forms.

3.2 Oral Administration It may seem paradoxical, but even with highly extracted drugs the AUC (or apparent clearance,

79

dose/ AUC) after oral administration depends more, if not entirely, on the activity of the hepatic drug metabolising enzymes and not on liver blood flow. This occurs because AUCoral is determined both by presystemic extraction and by the subsequent clearance from the systemic circulation, and these change in opposite directions when liver blood flow is changed. For example, when flow is reduced, presystemic extraction increases, but the ability of the liver to clear the smaller amounts that reach the systemic circuit is reduced (Wilkinson and Shand, 1975; Nies and Shand, 1976). While the direction of these changes is established beyond doubt, precise quantitative predictions are dependent on the model of hepatic clearance chosen. According to the 'venous equilibration' model of Rowland et aJ. (I 973), it can easily be shown that AUCoral is unchanged by liver blood flow and, furthermore, that apparent oral clearance (D/ AUCJ is numerically equal to intrinsic clearance, an estimate of enzyme activity (Wilkinson and Shand, 1975). Animal data suggest that this model describes the situation with propranolol (Branch et ai., 1973; Shand et al., 1975). The other 'sinusoidal' model originally proposed by Brauer (I 963), and which provides a good description of galactose kinetics (Keiding et al., 1976), suggests that AUC o will rise somewhat with reduced flow and vice versa. Nevertheless, even this model predicts lesser changes with blood flow alterations after oral compared with intravenous administration. A very full comparison of these models is provided by Pang and Rowland (I 977). Given that oral propranolol clearance depends on hepatic drug metabolising enzyme activity, which is known to vary quite widely (Vessel, 1977), it is not surprising that plasma propranolol concentrations varied more widely after single oral doses C7-fold) than after intravenous doses (2-fold) in the same young volunteers (Shand et al., 1970). As mentioned, the hepatic extraction falls to an intermediate value of about 66 % at steady-state. Variability, however, was still greater after oral administration O-fold) than after intravenous administration (I. 6-fold) in 6 young adults (Evans and Shand, 1973a). In larger popula-

Clinical Pharmacokinetics of Propranolol

tions, variations of up to 4- (Chidsey et at, 1975) or 20-fold (Shand, 1974) have been reported. Most recently we have found a IO-fold variation in normal volunteers (fig. I). Such variability is generally considered to result from genetic differences, superimposed upon which are certain constitutional and environmental factors such as age, smoking and diet (Vessel, 1977). Influence of Age, Smoking and Diet: In the paediatric age group, scaling down the dose on a body weight basis produces similar average plasma concentrations to those seen in young adults, but variability remains high (Wilson et aI., 1976). Castleden et al. (J 975) were the first to show that higher plasma propranolol concentrations were achieved in elderly compared with young adults after single oral doses. This difference was maintained during continued oral administration (Castleden and George, 1979). Vestal et al. (1 979b) have recently investigated the effects of age on propranolol disposition and found that these were complicated by smoking habits. While clearance after oral administration fell with age in smokers, this was not the case in nonsmokers. Interestingly, the effect in smokers was large enough to give a significant relationship with age in the group as a whole. The data suggest that the stimulating effects of smoking on drug metabolism are attenuated in the elderly. It should be mentioned that the data of Castleden and George were not biased by smoking habits, since only one of their subjects smoked. Whether the discrepancy involves racial differences, dietary differences or differing environmental exposures is not at all clear. This leads us to the most interesting discrepancy of all. Walle et al..(1 978a) have just reported an extremely narrow variation of plasma propranolol concentrations of only 1- to 3-fold in patients receiving the same dose of oral propranolol on a long term basis. Their study involved 46 patients with hypertensive or coronary artery disease who were hospitalised to ensure compliance and fed an isocaloric diet. In seeking to reconcile these findings with the data shown in figure I, we can safely exclude blood collection methods and compliance. For the reasons dis-

80

cussed previously, we do not feel differences in analytical methodology to be responsible. Nor were there material differences in age or smoking habits and Walle and colleagues confirmed an effect of smoking but not of age or concomitant drug administration. Since both groups were studied in the fasting state, one is left with the difference in the rigid diet of the Walle et al. (1978) study and no control in the investigation by Vestal et al. (l979b). Although diet is known to influence drug metabolism (Conney et aI., 1976; Kappas et at, 1976; Pantuck et aI., 1979), the effect seems surprisingly large and merits further investigation. What is clear is that a multitude of constitutional and environmental factors can influence pharmacokinetics even in normal adults, and that this will necessitate much larger study groups than previously used to elucidate the influence of any single factor. Influence of Food: An increased bioavailability of propranolol (as well as metoproloO w~s observed in 7 volunteers who took a single80mg dose with a standard breakfast and in the fasting state (Melander et aI., 1977). Bioavailability is dependent on liver blood flow as well as intrinsic clearance and it is known that an increase in hepatic blood flow occurs postprandially. It has been postulated that such an increase may cause a fall in the extraction ratio exclusively during the absorption phase, the effect of which more than compensates for the increase in the average clearance of propranolol during the whole dosage interval (McLean et al., 1978). This would result in an increased AVC and therefore an increased bioavailability. It should be mentioned, however, that Vervloet and co-workers (1978) and Walle and colleagues (J 978a) have not observed any increase in propranolol bioavailability with food intake in their studies. Influence of Altered Binding: So far, we have considered variability in total drug concentrations after oral administration. It is known, however, that it is the free drug concentration in body water that determines the ~-blocking effects of propranolol (McDevitt et al., 1976), so that alterations in drug binding are potentially of great importance. In the presence of

81

Clinical Pharmacokinetics of Propranolol

variable drug binding in blood, the appropriate index of drug metabolising enzyme activity is the intrinsic clearance of free drug (ClO, in which case, the apparent oral clearance of total drug may be expressed as (Wilkinson and Shand, 1975): D

-

AUC o

= Cli'fB

(Eq. I)

so that free drug concentrations are given by: D AUCofB = - Cli'

(Eq. 2)

From this relationship it is clear that for any given dose and intrinsic clearance, free drug concentrations will be unaltered by changes in binding, even though total drug concentrations are markedly changed. Thus, unlike the case with intravenous administration, after oral administration this situation resembles the classic teaching for restrictive elimination. Relationship oj Half-life to Clearance: Before leaving individual variation after oral administration, we should consider the determinants of half-life. This parameter depends on both volume of distribution and the systemic clearance of that part of the dose which escapes presystemic elimination. Because of the non-linear nature of the kinetics of propranolol, systemic clearance during continued oral administration is less than that after a single intravenous dose, and can only be measured by giving a tracer intravenous dose at steady-state. Using this technique, Kornhauser et al. (I 978) were able to show that the hepatic extraction of the drug is approximately 65 % , under which conditions both intrinsic clearance and blood flow will influence systemic clearance and halflife. Intrinsic clearance remained high enough that plasma binding differences over the normal range did not affect systemic clearance. Such changes would, however, influence drug half-life by affecting volume of distribution in the same way as they do after intravenous administration. The technique of Kornhauser et al. (I 978) is a particularly powerful one as it can be used to estimate all the biological determinants of the disposition of

propranolol, including hepatic blood flow. It has therefore been applied quite extensivelY by that group in an attempt to relate changes produced by constitutional and environmental factors, drug interactions and disease to known alterations in physiology and pathology. For example, the known reduction in liver blood flow with aging (Sherlock et aI., 1950) has been confirmed (Vestal et aI., I 979b). This would explain the negative correlation between the clearance of indocyanine green (a highly extracted drug) and age (Wood et aI., I 979b). The previously described effects of smoking and age on the intrinsic (oral) clearance of propranolol were also seen with antipyrine, elimination of which is rate limited by enzyme activity (Wood et aI., I 979b). Finally, it was shown that the effects of age and smoking on intrinsic clearance and blood flow produced the predicted changes in the systemic clearance of propranolol during continued oral administration (Vestal et aI., I 979b).

4. Pharmacokinetic Drug Interactions Because propranolol possesses little dose related toxicity, it is difficult to detect possible interactions in the clinical situation. It is possible that a change in the degree of ~-blockade could affect the control of angina, arrhythmias or blood pressure in a patient already stabilised on propranolol, but it would be difficult to identify a drug/drug interaction among all the other variables. It is interesting to note that one of the two propranolol interactions described below was documented after in vitro animal experiments suggested the likelihood of such a phenomenon, while the other study was performed because the interacting drug (halofenate) had already been shown to markedly affect the disposition of other drugs metabolised by similar pathways. In 4 subjects receiving continued oral doses of propranolol, the plasma propranolol concentration was significantly lower during concomitant halofenate administration compared with placebo. This was associated with decreased ~-adrenoceptor blockade, indicating that the free plasma propranolol

Clinical Pharmacokinetics of Propranolol

82

concentration also fell, although this was not measured in the study (Huffman et aI., 1976). The most likely explanation for this interaction is that halofenate increases the intrinsic (ora!) clearance of propranolol. Although a decrease in propranolol absorption is another possible explanation, this is much less likely since propranolol is normally so well absorbed (Paterson et aI., 1970), and absorption interactions normally occur with drugs whose absorption is less than optimal. In contrast, the steady-state blood propranolol concentrations were consistently increased in 5 normal subjects during concomitant oral administration of chlorpromazine 50rng 8-hourly, compared with during oral administration of propranolol alone. The protocol of Kornhauser et al. (J 978) was followed and it was thus also possible to estimate bioavailability, which rose, and liver blood flow, which remained constant during chlorpromazine administration. As predicted, changes in systemic clearance were less, and in fact, not significant. Drug half-life, volume of distribution and plasma propranolol binding were unaffected. In only 2 of 4 patients studied was the change in oral plasma propranolol great enough, however, to produce significant changes in isoprenaline (isoprotereno!) sensitivity and/ or plasma renin activity. Since propranolol is essentially completely absorbed in normal individuals, enhancement of absorption could not occur so that the most likely explanation for the interaction is the fall in intrinsic total (and intrinsic free) clearances caused by chlorpromazine administration (Vestal et aI., 1979b).

5. Pharmacokinetics in Disease 5. I Liver Disease Since the liver appears to be the only site of propranolol metabolism in man, liver disease would be expected to have a marked effect on propranolol disposition and this is indeed the case. Liver disease can affect all four biological determinants of propranolol disposition: intrinsic clearance, hepatic

----~-

blood flow, drug binding and the anatomical arrangement of the hepatic circulation (Branch and Shand, 1976). The effects of acute hepatic disease have not been documented so that the following studies all concern patients with chronic cirrhosis of variable degree. The most comprehensive study involved 9 normal subjects and 7 patients with biopsy proven, well compensated cirrhosis and the technique described by Kornhauser et al. (J 978) was used to simultaneously determine the oral and intravenous pharmacokinetics (Wood et aI., 1978b). In cirrhosis, bioavailability was increased and plasma binding decreased so that total and free steady-state blood propranolol concentrations were markedly higher, ess (free) being approximately 3-fold greater. The volume of distribution was increased in cirrhosis and the systemic (intravenous) clearance reduced. The probable presence of mesenteric shunts precluded the estimation of true intrinsic (ora!) clearance and liver blood flow, although the 'apparent' intrinsic clearance was reduced and the 'apparent' liver blood flow unchanged. It was therefore concluded that the most likely major cause of the increase in steady-state blood propranolol concentration in cirrhosis was a reduced intrinsic clearance and/or mesenteric shunting. This conclusion is supported by the work of Pessayre and colleagues (I978) who measured the pharmacokinetics of the dextro entantiomer of propranolol in control subjects, patients with alcoholic fibrosis (without cirrhosis) and those with alcoholic cirrhosis. Subsequent hepatic vein catheterisation in the cirrhotic and some of the fibrotic patients, allowed estimation of the extraction ratio and intrinsic hepatic clearance (Pessayre et aI., 1978). Liver blood flow was measured by infusing indocyanine green (Caesar et aI., 1961). It was concluded that the reduced systemic clearance of d-propranolol in patients with cirrhosis was predominantly due to a decrease in intrinsic clearance with a minor component due to decreased liver blood flow. Although the systemic clearance of d-propranolol is slightly higher than the racemic mixture (George et aI., 1972), possibly because it is devoid of ~-adrenoceptor blocking

-----~---

Clinical Pharmacokinetics of Propranolol

activity and does not reduce liver blood flow (Nies et aI., 1973), its other pharmacokinetic properties are similar. Changes in disposition of d-propranolol are therefore likely to reflect changes in the pharmacokinetics of d,l-propranolol. 5.2 Renal Disease Studies on the disposition of propranolol in renal disease do not provide complete pharmacokinetic data. However, it appears that maximum blood or plasma concentrations achieved after an equivalent single oral dose was 2- to 3-fold higher in patients with chronic renal disease (Lowenthal et aI., 1974), but was normal in those on regular dialysis (Bianchetti et aI., 1976). Absorption also appeared to be more rapid with maximum propranolol concentrations appearing at 1.5 'rather than 2 hours. Intrinsic (oral) clearance was diminished in those patients not receiving regular dialysis and calculated bioavailability was therefore significantly greater (Bianchetti et aI., 1976). Interestingly, the binding of propranolol may actually increase slightly in patients with renal disease (Piafsky et aI., 1978), although the decrease in free fraction would be too small to offset the increased total blood propranolol concentration seen in the studies mentioned. Free propranolol concentrations would still be increased, therefore, in patients with chronic renal disease. It has recently been reported, however, that after multiple doses of propranolol, mean plasma propranolol concentrations may fall in patients with chronic renal disease and enzyme induction has been suggested as a possible mechanism (Lowenthal and Mutterperl, 1976). Our own experience (Wood, Vestal, Spanneth, Stone and Shand, unpublished) suggests no difference in steady-state kinetics in renal failure compared with age matched controls. 5.3 Thyroid Disease Information relating to the pharmacokinetics of propranolol in thyroid disease is also incomplete.

83

Systemic (intravenous) clearance of propranolol certainly appeared to be increased by 50 % in IS hyperthyroid patients (Graves' disease) compared with IS controls, although details of relative ages of the 2 groups were not given. The systemic clearance was also significantly related to the T 3 serum level in the hyperthyroid patients (Rubenfeld et aI., 1978). The cardiac output is increased in hyperthyroidism and this would increase liver blood flow. Since systemic clearance is related to liver blood flow, this is a possible explanation for the difference in systemic clearance between the 2 groups. Oral clearance depends only on the intrinsic clearance and is independent of liver blood flow. Clearance of orally administered doses of propranolol should not, therefore, be altered unless intrinsic clearance changes. Two single dose oral studies have also been published. No difference was found between 8 hyperthyroid patients and 4 age matched hypothyroid patients in the oral (intrinsic) clearance of I OOmg of propranolol (Bell et al., 1977). Peak plasma concentrations were achieved significantly more quickly in the hyperthyroid (I3 hours) patients compared with the hypothyroid patients 0.5 hours) however. Similarly, no difference in the peak propranolol levels or elimination half-lives was detected between the 15 hyperthyroid and 15 normal subjects whose systemic clearances (described earlier) were obviously different, although details of age and smoking habits are absesent (Rubenfeld et aI., 1978). These findings contrast with the results in I I hyperthyroid patients before and 10 to 14 days after partial thyroidectomy. The 4 hour plasma propranolol concentration at 'steady-state' postoperatively was double the corresponding value before operation, consistent with increased drug metabolism in the hyperthyroid state (Feely and Stevenson, 1978a). Conversely, the same group have shown that propranolol levels fall when hypothyroid patients are treated with thyroxine. They have also documented the changes in propranolol concentration perioperatively and it is clear that major alterations in propranolol disposition are occurring (Feely and Stevenson, 1978b). In 22 hyperthyroid patients, there

Clinical Pharmacokinetics of Prop!anolol

was a fall in propranolol concentrations immediately postoperatively with a further fall at 8 hours after operation, even though most of the patients had been given a propranolol maintenance dose during that period. Continuation of propranolol therapy resulted in a marked increase in the propranolol concentration at 24 hours after operation which fell over the following 3 to 5 days. The marked rise in plasma propranolol concentrations might be due to the operative and anaesthetic insult reducing intrinsic clearance, which resolved over the next 3 to 5 days. The plasma protein binding of propranolol, measured by equilibrium dialysis, was not significantly different in 7 hyperthyroid patients compared with 10 hypothyroid patients (Kelly and McDevitt, 1977).

5.4 Hypertension The effects of hypertension of propranolol disposition are complicated by the effects of the disease on renal function. It is therefore important to include only hypertensives with no reduction in renal function. Weiss and co-workers (J 976) found a much greater systemic (intravenous) clearance of propranolol in 'borderline' compared with 'permanent' hypertensives. Separation into the 2 .groups was made solely on the basis of severity and consistency of hypertension and, almost by definition, the borderline hypertensives would be younger than the permanent hypertensives, although no ages are given. Liver blood flow is known to decrease with increasing age, and this factor is one of the determinants of systemic clearance. Indeed, the correlation between cardiac output and systemic propranolol clearance (r = 0.96) indicates that over 90 % of the variation in propranolol clearance could be attributed to variation in cardiac output (and therefore liver blood flow). Another interesting finding is that totai propranolol clearance was 2-fold higher in the 'borderline' hypertensives, whereas the cardiac output was only 25 % greater. Since the extraction ratio of highly cleared drugs falls slightly with increasing hepatic blood flow

84

the authors suggest that this could indicate a redistribution of blood flow in the 'borderline' group, so that a larger proportion of the total cardiac output is directed through the liver. Since oral clearance is not dependent on hepatic blood flow, the oral disposition of propranolol in borderline or permanent hypertensives would not be expected to differ from normal volunteers, but no data are available to clarify this theoretical concept.

5.5 Gastrointestinal Disease Abnormalities of propranolol pharmacokinetics have been seen in patients with coeliac disease and Crohn's disease. Peak plasma propranolol concentrations were achieved earlier (J hour) in 8 patients with coeliac disease than in 12 normal volunteers (2 hours) after oral administration of40mg propranolol, but AVC was not significantly different between the 2 groups (Schneider et aI., 1976). In a similar study of 14 patients with coeliac disease and I 0 controls, peak plasma propranolol concentrations occurred at 1.5 hours in coeliac disease patients and 2 hours in healthy volunteers (Parsons et aI., 1976). AVC was significantly greater in coeliac patients when the data were analysed by the method of Saunders and Natunen (J 973) but not when the method of Wagner and Nelson (J 964) was used. Although the control group was younger (27 years) than the coeliac patients (45 years) the authors felt that age differences did not account for these effects, since there was no significant difference in the mean propranolol concentration between the older and younger coeliac patients. Both studies used plasma propranolol concentrations rather than whole blood concentrations. A difference in the blood/ plasma propranolol concentration ratio caused by altered plasma protein binding and/ or differences in the haematocrit in coeliac disease could therefore result in differences in the plasma propranolol clearance, which might not be related to concomitant differences in whole blood propranolol clearance.

85

Clinical Pharmacokinetics of Propranolol

Schneider and co-workers (I 976) also administered a single oral dose of propranolol (40mg) to 10 patients with Crohn's disease. Peak plasma concentrations were achieved at I hour and the AVC was significantly increased. However, the plasma free fraction of propranolol in 12 patients with Crohn's disease (6.3 %) was almost half that of 25 normal controls (10.7 %) [Borga et aI., 1977], which would at least contribute to the difference in AVC between the patients with Crohn's disease and normal volunteers. It is known that hepatic disease can complicate Crohn's disease and it is interesting that the largest AVe's were found in those patients with the highest erythrocyte sedimentation rates. It is not unexpected that the oral propranolol clearance also falls in such patients. A preliminary report indicates that patients with other diseases in which the erythrocyte sedimentation rate is abnormally high (e.g. rheumatoid arthritis and ulcerative colitis) may have a diminished oral clearance of propranolol (Babb et aI., 1976).

5.6 Malnutrition Recently, a significant increase in the elimination half-life of propranolol was observed in 8 undernourished Kenyans compared with 8 mildly hypertensive patients matched fl?r age, tribe and sex (Obel and Vere, 1978). The prolonged half-life was present after single doses and at steady-state. However, halflife is dependent on the volume of distribution as well as the elimination rate of the drug and could be increased, if plasma propranolol binding was decreased in the undernourished patients, without any change in intrinsic clearance. In contrast, only 5 to I 0 % of plasma antipyrine is bound to protein and administration of this drug to both groups revealed no difference in apparent volume of distribution (which approximates total body water) yet the half-life was also markedly increased in the subjects with malnutrition. This suggests that the increase in propranolol halflife was also probably due to diminished intrinsic clearance, although the relationship between the propranolol half-life and the corresponding antipyrine

half-life in each patient was not given. Although the half-lives were calculated with data points only up to 4 hours, the mean half-lives of propranolol and antipyrine in the control group are close to previously reported normal values.

5.7 Hypothermia It ,was recently noted that the plasma propranolol levels in patients undergoing cardiac surgical procedures under hypothermia had higher plasma propranolol levels than predicted from the drug's kinetics during normothermia. Inhibition of metabolism alone could not account for the rise in plasma levels. In dogs, systemic kinetics showed a marked contraction of the distribution volume as a result of hypothermia which accounted for the higher plasma propranolol concentrations during the hypothermic state (McAllister et aI., 1979). The situation in patients undergoing open heart surgery may well be more complex, however, because the administration of heparin to these individuals may reduce propranolol plasma binding and thus affect the volume of distribution (Wood et al., I 979a).

6. Clinical Significance ofAltered Kinetics The pharmacokinetics of propranolol are undoubtedly complex and it is fair to say that the unravelling of their complexity has contributed to our knowledge of pharmacokinetics and drug disposition in general. But what of the relevance to the clinical use of the drug? The clinical application of kinetic data is most important for drugs with a narrow therapeutic ratio and whose effects are difficult to monitor accurately. This is certainly not true of propranolol which, apart from the precipitation of heart failure that occurs with small doses early in the course of treating susceptible patients and asthma in susceptible individuals which is unpredictable, has little serious dose related toxicity. Thus, kinetic alterations raising plasma concentrations are not of great importance,

Clinical Pharmacokinetics of Propranolol

86

though lowering of concentrations (for example by enzyme induction) might be. Furthermore, reasonable clinical endpoints exist for most of the drug's indications. What is important is that the dosage requirement for propranolol varies very widely indeed. Variable plasma levels after a given dose probably contribute to this and any meaningful study of dose/ response relationships must include plasma .concentration determinations and, preferably, a measure of free drug concentration.

7. Plasma Concentration and Clinical Effect Relationship Several studies have addressed the relationship of plasma concentration to ~-blockade as well as to the therapeutic effects of propranolol, with mixed results. The most thorough studies suggest that a very high degree of cardiac ~-blockade is produced by plasma concentrations of the order of 75 to I OOng/ ml in young volunteers (Coltart and Shand, 1970; Pine et aI., 1975) and that these levels are also effective in angina, a situation in which we can ascribe the major effect of the drug to its actions on the heart. The situation in the treatment of ventricular arrhythmias and hypertension is confounded by our lack of knowledge of the exact mechanism of action of the drug. Recent data suggest that some patients with ventricular arrhythmia (W oosley et aI., I 977) and low renin hypertension (Hollifield et aI., 1976) require plasma concentrations greatly in excess of I OOng / mI. Interestingly, in some patients with ventricular ectopic beats increasing to concentrations greater than 100ng/ml were associated a recrudescence of a previously controlled arrhythmia (Woosley et aI., 1977). Whether the need for higher concentrations is due to differing mechanisms of action, as suggested, to inaccessibility of drug to its site of action, or to variable receptor sensitivity to any given drug concentration is unclear. The fact that it has recently been found that elderly people are less sensitive to a given free propranolol concentration does suggest that difference in receptor sensitivity does exist and may con-

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tribute to individual differences in the plasma 'eoncentration/effect relationship (Vestal et aI., I 979c). Given these uncertainties, it is not surprising that a meaningful range of effective plasma concentrations has not been firmly established. Currently, we can only recommend plasma concentration monitoring as a test of compliance in patients receiving large doses without apparent benefit. Then very low levels ( <20ng/ mn and failure of these to rise with increased dosage make non-compliance likely. It is also likely that a patient with angina who has demonstrated no response with levels of 1OOng/ ml at the end of the dosage interval represents a real therapeutic failure. In the ease of arrhythmias and hypertension, with definable clinical endpoints, it is necessary only to recognise that the effective dose can vary quite widely.

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Clinical Pharmacokinetics of Propranolol

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Evans, G.H. and Shand, D.G.: Disposition of propranolol. V. Drug accumulation and steady-state concentrations during chronic oral administration in man. Clinical Pharmacology and Therapeutic~ 14: 487-493 (I973a). Evans, G.H. and Shand, D.G.: Disposition of propranolol. VI. Independent variation in steady-state circulation drug concentrations and half-life as a result of plasma drug binding in man. Clinical Pharmacology and Therapeutics 14: 494-500 (] 973b). Evans, G.H.; Wilkinson, G.R. and Shand, D.G.: The disposition of propranolol. IV. A dominant role for tissue uptake in the dose-dependent extraction of propranolol by the perfused rat liver. Journal of Pharmacology and Experimental Therapeutics 186: 447-454 (I 973b}. Feely, J. and Stevenson, I.H.: The effect of age and hyperthyroid on plasma propranolol steady state concentration. British Journal of Clinical Pharmacology 6: 446P (] 978a). Feely, J. and Stevenson, I.H.: Effect of partial thyroidectomy on plasma propranolol steady state concentration. The International Congress of Pharmacology, Paris, July 16-21, Abstract (I978b). Fitzgerald, J.D. and O'Donnell, S.R.: Pharmacology of 4-hydroxy propranolol, a metabolite of propranolol. British Journal of Pharmacology 43: 222-235 (] 97 J). Fremstad, D.: Reduced binding of quinidine in plasma from Vacutainers. Clinical Pharmacology and Therapeutics 20: 120 (I 976) correspondence. George, C.F.; Fenyvesi, T.; Conolly, M.E. and Dohery, C.T.: Pharmacokinetics of dextro, laevo and racemic propranolol in man. European Journal of Clinical Pharmacology 4: 74-77 (I 972}. Gibaldi, M.; Boyes, R.N. and Feldman, S.: Influence of first-pass effect on availability of drugs on oral administration. Journal of Pharmaceutical Sciences 60: 1338-1340 (I 97 J). Gomeni, I.R.; Bianchetti, G.; Seager, R. and Morselli, P.L.: Pharmacokinetics of propranolol in normal healthy volunteers. Journal of Pharmacokinetics and Biopharmaceutics 5: 183-192 (I977). Hayes, A. and Cooper, R.G.: Studies on the absorption; distribution and excretion of propranolol in various species. Journal of Pharmacology and Experimental Therapeutics 176: 302-311 (I97]). Hollifield, J.W.; Sherman, K.; Zwagg, R.V. and Shand, D.G.: Proposed mechanisms of propranolol's antihypertensive effect in essential hypertension. New England Journal of Medicine 295: 68-73 (I976). Huffman, D.H.; Azarnoff, D.L.; Shoeman, D.W. and Dujovne, C.A.: The interaction between halofenate and propranolol. Clinical Pharmacology and Therapeutics 19: 807-812 (I 976). Jellet, L.B. and Shand, D.G.: Uptake of propranolol by washed human red cells. Pharmacologist 15: 245 (I 973). Johnsson, G. and Regardh, C.G.: Clinical pharmacokinetics of ~­ adrenoceptor blocking drugs. Clinical Pharmacokinetics I: 233-263 (I 976}.

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Kappas, A.; Anderson, K.E.; Conney, A.H. and Alvares, A.P.: InMisson. A.W. and Dickson, 5.1.: Contamination of blood samples fluence of dietary protein and carbohydrate on antipyrine and by plasticizer in evacuated tubes. Clinical Chemistry 20: 1247 (1974). theophylline metabolism in man. Clinical Pharmacology and Therapeutics 20:643-652 (1976). Myers. M.G.; Lewis. P.J.; Reid, J.L. and Dollery. C.T.: Brain conKawashima, K.; Levy, A. and Spector, S.: Stereospecific radio-imcentration of propranolol in relation to hypertensive effect in munoassay for propranolol isomers. Journal of Pharmacology the rabbit with observations on brain propranolol levels in and Experimental Therapeutics 196: 517-523 (1976). man. Journal of Pharmacology and Experimental Therapeutics Keiding, S.; Johansen, S.; Winkler, K.; Tonensen, K. and 192: 327-335 (\975). Tygstrup, N.: Michaelis-menten kinetics of galactose eliminaNation. R.L.; Peng, G.W. and Chiou. 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Clinical Pharmacokinetics of Propranolol

Pine. M.; Favrot. L.; Smith. S.; McDonald. K. and Chidsey. C.A.: Correlation of plasma propranolol concentration with therapeutic response in patients with angina pectoris. Circulation 52: 886-893 (J 975). Rowland. M.: Influence of route of administration on drug availability. Journal of Pharmaceutical Sciences 61: 70-74 (J 972). Rowland. M.; Benet. L.Z. and Graham. G.: Clearance concepts in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics I: 123-136 (J 973). Rubenfeld. S.; Silverman. V.E.; Welch. K.M.A.; Mallette. L.E. and Kohler. P.O.: Propranolol pharmacokinetics in thyrotoxicosis. Clinical Research 26: 295A (J 978). Sager. G.; Nilson. O.G. and Jacobsen. S.: Distribution of propranolol in blood. International Congress of Pharmacology. July 16-21. Abstracts. ,p.280 (J 978). Saunders. L. and Natunen. T.: A stable method for calculating oral drug absorption rate constants with two compartment disposition. Journal of Pharmacy and Pharmacology 25: 44P-51P (J 973). Schneider. R.E.; Babb. J.; Bishop. H.; Mitchard. M. and Hoare. A.M.: Plasma levels of propranolol in treated patients with coeliac disease and patients with Crohn's disease. British Medical Journal 2: 794-795 (J 976). Shand. D.G.: Individualization of propranolol therapy. Medical Clinics of North America 58: 1063-1069 (J974). Shand. D.G.; Branch. R.A.; Evans. G.H.; Nies. A.S. and Wilkinson. G.R.: The disposition of propranolol. VII. The effects of saturable hepatic tissue uptake on drug clearance by the perfused rat liver. Drug Metabolism and Disposition I: 679-686 (J 97 3). Shand. D.G.; Kornhauser. D.M. and Wilkinson. G.R.: Effects of route of administration and blood flow on hepatic drug elimination. Journal of Pharmacology and Experimental Therapeutics 195: 424-432 (I 975). Shand. D.G.; Nuckolls. E.M. and Oates. J.A.: Plasma propranolol levels in adults. with observations in four children. Clinical Pharmacology and Therapeutics II: 112-120 (J 970). Shand. D.G. and Rangno. R.E.: The disposition of propranolol. I. Elimination during oral absorption in man. Pharmacology 7: 159-168 (J 972). Sherlock. S.; Beam. A.G.; Billing. B.H. and Paterson. J.C.S.: Splanchnic blood flow in man by the bromsulfalein method. The relation of peripheral plasma bromsulfalein level to the calculated flow. Journal of Laboratory and Clinical Medicine 35: 923-932 (J 950). Simon. M. and Babich-Armstrong. M.: Propranolol in serum by HPLC. Clinical Chemistry. submitted (J 979). Stargel. W.W.; Roe. C.R.; Routledge. P.A. amd Shand. D.G.: Importance of blood collection tubes in plasma lidocaine determinants. Clinical Chemistry. In press (J 979). Suzuki. T.; Isozaki. S.; Ishida. R.; Saitoh. Y. and Nakagawa. F.: Drug absorption and metabolism studies by use of portal vein

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infusion in the rat. II. Influence of dose and infusiol). rate on the bioavailability of propranolol. Clinical Pharmacology Bulletin 22: 1639-1645 (1974). Suzuki. T.; Saitoh. Y.; Isozaki. S. and Ishida. R.: Drug absorption and metabolism studies by use of portal vein infusion in the rat. I. Pyloric vein cannulation and its application to study of first-pass effect. Chemical Pharmaceutical Bulletin 20: 2731-2735 (1972). Vervloet. E.; Takx-Kohlen. B.C.MJ.; Pluym. B.F.M. and Merkus. F.W.H.M.: Blood plasma concentration ratio of propranolol. Clinical Pharmacology and Therapeutics 23: 133 (J 978). Vessel,' E.S.: Genetic and environmental factors affecting drug disposition in man. Clinical Pharmacology and Therapeutics 22: 659-679 (J 977). Vestal. R.E.; Kornhauser. D.M.; Hollifield. J.W. and Shand. D.G.: Inhibition of propranolol metabolism by chlorpromazine. Clinical Pharmacology and Therapeutics 25: 19-24 (J 979a). Vestal. R.E.; Wood. AJJ.; Branch. R.A.; Shand. D.G. and Wilkinson. G.R.: The effects of aging and cigarette smoking on propranolol's disposition in man. Clinical Pharmacology and Therapeutics. submitted (J 979b). Vestal. R.E.; Wood. A.J.J. and Shand. D.G.: Reduced ~ adrenoceptor sensitivity in the elderly. Clinical Pharmacology and Therapeutics. submitted (J 979c). Wagner. J.G. and Nelson. E.: Kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug. Journal of Pharmaceutical Sciences 53: 1392-1403 (J 964). Walle. T.: GLC determination of propranolol. other ~-blocking drugs. and metabolites in biological fluids and tissues. Journal of Pharmaceutical Sciences 63: 1885-1891 (1974). Walle. T.; Conradi. E.; Walle. K.; Fagan. T. and Gaffney. T.E.: Steady-state kinetics of the active propranolol metabolite. 4hydroxypropranolol and its glucuronic acid conjugate in patients with hypertension and coronary artery disease. Clinical Research 25: lOA (J 977). Walle. T.; Conradi. E.C.; Walle. U.K. and Gaffney. T.E.: Steadystate plasma concentrations and urinary excretion of propranolol-o-glucuronide and propranolol in patients during chronic oral propranolol therapy. Federation Proceedings 35: 665 (J 976). Walle. T.; Conradi. E.C.; Walle. K.; Fagan. T.C. and Gaffney. T.E.: The predictable relationship between plaSma levels and dose during chronic propranolol therapy. Clinical Pharmacology and Therapeutics 24: 668-677 (J 978a). Walle. T.; Conradi. E.C.; Walle. U.K. and Gaffney. T.E.: 0methylated catechol-like metabolites of propranolol in man. Drug Metabolism and Disposition 6: 481-487 (J 978b). Walle. T. and Gaffney. T.E.: Propranolol metabolism in man and dog: Mass spectrometric identification of six new metabolites. Journal of Pharmacology and Experimental Therapeutics 182: 83-92 (1972).

Clinical Pharmacokinetics of Propranolol

Walle, T.; Morrison, J.; Walle, K. and Conradi. E.: Simultaneous determination of propranolol and 4-hydroxypropranolol in plasma by mass fragmentography. Journal of Chromatography 114: 35i-359 (975). Weiss, Y.A.; Safar, M.E.; Chevillard, c.; Frydman, A.; Simon. A.; Lemaire, P. and Alexandre, J.M.: Comparison of the pharmacokinetics of intravenous dl-propranolol in borderline and permanent hypertension. European Journal of Clinical Pharmacology 10: 387-393 (1976). Weiss, Y.A.; Safar, M.E.; Lehner, J.P.; Levenson, J.A.; Simon, A. and Alexandre, J.M.: (d)-Propranolol clearance, an estimation of hepatic blood flow in man. British Journal of Clinical Pharmacology 5: 457 -460 (1978). Wilkinson, G.R. and Schenker, S.: Pharmacokinetics of meperidine in man. Clinical Pharmacology and Therapeutics 20: 120 (1976). Wilkinson, G.R. and Shand, D.G.: A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377-390 (1975). Wilson, J.T.; Atwood, G.F. and Shand, D.G.: Disposition of prepoxyphene and propranolol. Clinical Pharmacology and Therapeutics 19: 264-270 (1976). Wood, AJ,J.; Carr, K.; Vestal, R.E.; Belcher, S.; Wilkinson, G.R. and Shand, D.G.: Direct measurement of propranolol bioavailability during accumulation to steady state. British Journal of Clinical Pharmacology 6: 345-350 (l978a).

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Wood, AJJ.; Kornhauser, D.M.; Wilkinson, G.R.; Shand, D.G. and Branch, R.A.: The influence of cirrhosis on steady-state blood concentrations of unbound propranolol after oral administration. Ciinical Pharmacokinetics 3: 478-487 (j 978bi. Wood, M.; Shand, D.G. and Wood, AJ.J.: Altered drug binding due to the use of indwelling heparinised canulae (heparin-lock) for sampling. Clinical Pharmacology and Therapeutics 25: 103-107 (I 979a). Wood, A.J.J.; Vestal, R.E.; Wilkinson, G.R.; Branch, R.A. and Shand, D.G.: The effect of aging and cigarette smoking on the elimination of antipyrine and indocyanine green. Clinical Pharmacology and Therapeutics, submitted (l979b). Woosley, R.L. and Shand, D.G.: Pharmacokinetics of antiar~ rythmic drugs. American Journal of Cardiology 41: 986-995 (1978). Woosley, R.L.; Shand, D.G. and Kornhauser, D.M.: Relation of plasma concentration and dose of propranolol to its effect on ventricular arrhythmias. Clinical Research 25: 262A (1977).

Author's address: Dr D.G. Shand, Division of Clinical Pharmacology, Box 3813 Duke University Medical Center, Durham, North Carolina 27710 (USA).

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