The effects of enzyme induction and enzyme inhibition on labetalol pharmacokinetics

Transcription

1 Br. J. clin. Pharmac. (1984), 18, The effects of enzyme induction and enzyme inhibition on labetalol pharmacokinetics T. K. DANESHMEND* & C. J. C. ROBERTS University Department of Medicine, Bristol Royal nfirmary, Bristol, BS2 8HWW 1 The oral and intravenous pharmacokinetics of labetalol were determined in five subjects before and after a 3 week course of glutethimide 500 mg/day. After glutethimide there was a significant reduction in the AUC after the oral dose of labetalol, from 40, ,534 (mean + s.e. mean) to 22, ,276 ng ml-' min (2P < 0.05), and systemic bioavailability was reduced from to 17.0 ± 3.5% (2P < 0.001). There was no significant change in labetalol plasma concentration-time curve (AUC) following an intravenous dose, half-life, volume of distribution, and plasma clearance. 2 The oral and intravenous pharmacokinetics of labetalol were determined in six subjects before and after a 3 day course of cimetidine 1.6 g/day. After cimetidine there was a significant reduction in the volume of distribution of labetalol, from to (2P < 0.05). The AUC of labetalol after the oral dose increased by 66%, from 51, ,950 to 84, ,444 ng ml-1 min (2P = 0.06). The systemic bioavailability of labetalol increased from 25.1 ± 2.4 to % (2P = 0.06). There was no significant change in labetalol AUC after the intravenous dose, half life, and plasma clearance. 3 There were no significant changes in resting heart rate and supine systolic and diastolic blood pressure following labetalol plus glutethimide, or labetalol plus cimetidine. One subject who took an oral dose of labetalol after a course of cimetidine developed postural hypotension. This subject had the highest plasma labetalol concentrations in this study. 4 Glutethimide and cimetidine alter the first pass metabolism of labetalol. These pharmacokinetic interactions should therefore be considered during clinical use of labetalol. Drugs known to alter the activity of microsomal oxidative enzymes, such as glutethimide and cimetidine, may also interfere with glucuronide conjugation. Keywords enzyme induction enzyme inhibition labetalol pharmacokinetics ntroduction The elimination of high clearance drugs may be inhibitor of hepatic microsomal oxidative enaltered by drugs which alter the activity of zymes such as the H2 receptor antagonist microsomal enzymes. The bioavailability of cimetidine (Puurunen & Pelkonen, 1979), inlignocaine and of paracetamol is reduced in creases the bioavailability of propranolol (Feely patients taking anticonvulsant drugs known to et al., 1981; Heagerty et al., 1981) and chlorproduce enzyme induction (Perucca & Richens methiazole (Desmond et al., 1981). Labetalol, a 1979a, b; Perucca et al., 1980). n contrast, an combined a- and,-adrenoceptor antagonist, * Present address: Department of Medicine, Freedom is lipid soluble and undergoes high first pass Fields Hospital, Plymouth PL4 7LY extraction in man (Martin et al., 1976; Homeida 393

2 394 T. K. Daneshmend & C. J. C. Roberts et al., 1978). However, unlike propranolol which is oxidised, labetalol is metabolised by conjugation to a glucuronide (Martin et al., 1976). Labetalol is thus one of the few high clearance agents which is eliminated by a phase reaction in man. n this study labetalol was used as a model compound to examine the effects of cimetidine (a microsomal enzyme inhibitor), and of glutethimide (a microsomal enzyme inducer) on the presystemic elimination of a drug metabolised by glucuronide conjugation. Methods Six male and three female healthy subjects took part in these studies which were approved by the hospital ethics committee. They were aged between 21 and 26 years and none smoked or was on any medication. The two studies were conducted as follows: (a) Labetalol-glutethimide study Labetalol kinetics were determined in five subjects following (i) labetalol 0 mg orally, and (ii) labetalol 0.5 mg/kg body weight given intravenously, in random order with an interval of 5 days. The subjects remained supine during the 6 h study period. The studies were conducted after an overnight fast. A light snack was allowed 4 h after the dose of labetalol. Venous blood samples were collected before the dose of labetalol and at 15, 30, 45, 60, 75, 90, 105, 1, 150, 180, 210, 240, 300 and 360 min after the dose. Plasma samples were frozen at - C for subsequent analysis of labetalol by a spectrofluorometric method (Martin et al., 1976). The lower limit of sensitivity of this assay was 15 ng/ ml of plasma. The coefficient of variation for this assay was 6%. Heart rate and blood pressure were measured in the supine position before the dose and half hourly for 4 h, then hourly for a further 2 h. After determination of baseline labetalol kinetics, each subject took glutethimide 500 mg orally every evening for 28 days. Labetalol kinetics were repeated as above in random order on the 23rd and 28th day of the course of glutethimide. (b) Labetalol-cimetidine study Labetalol kinetics were determined in six subjects as described above after oral and intravenous dosing. After these baseline labetalol kinetics, each subject took cimetidine 400 mg every 6 h, for 3 days on two occasions separated by 10 days. Labetalol kinetics were performed in random order on the fourth day of each treatment with cimetidine. Calculations The plasma half-life (t½,) of labetalol was calculated from least squares regression analysis of the terminal exponential log plasma concentration-time profile. The area under the plasma concentration-time profile (AUC) was calculated as follows: the area up to the end of sampling (x) was calculated using the trapezoidal rule; subsequent area extrapolated to infinity (y) was calculated from regression analysis of the terminal log concentration-time slope. Total AUC was x plus y. The apparent volume of distribution of labetalol (V) and the clearance of labetalol (CL) were calculated as follows from data following intravenous dosing: dose i.v. CL = AUC i.v. dose i.v. x t½, AUC i.v. x where dose i.v. was dose given intravenously and a constant. Systemic bioavailability (F) was calculated as: AUC oral x dose i.v. F= AUC i.v. x dose oral and expressed as a percentage. Student's t-test for paired data was used for statistical analysis. Signficance was assumed at 2P < Results (a) Labetalol-glutethimide study Composite labetalol concentration vs time plots before and after the 3 week course of glutethimide are shown in Figure 1. The pharmacokinetic measurements are summarised in Table 1. There was no significant change in labetalol half-life after oral and intravenous dosing, the volume of distribution, plasma clearance or the AUC of labetalol after intravenous dosing. There was a significant reduction in the AUC after the oral dose of labetalol. Systemic bioavailability was reduced by 43% after pretreatment with glutethimide. The peak labetalol concentrations were decreased from 4 ± 65 ng/ml (mean ± s.e. mean) to 117 ± 46 ng/ml (2P < 0.05). However there was no significant change in the time to reach peak labetalol concentrations. Supine heart rate and blood pressure were

3 300-0 Labetalol and enzyme induction and inhibition Pre-glutethimide Post-glutethimide T 395 E S T T T n0 CL Figure 1 Plasma labetalol concentrations (mean ± s.e. mean) in five healthy volunteers following administration of 0 mg orally (e) and 0.5 mg/kg body weight intravenously (0), before and after a 3 week course of glutethimide 500 mg daily. not significantly different following glutethimide pretreatment. However examination of the change in heart rate and blood pressure from the baseline values showed an attenuation of the hypotensive response to labetalol, especially after the oral dose (Figures 2 and 3). (b) Labetalol-cimetidine study Composite labetalol concentration vs time plots before and after the 3 day courses of cimetidine are shown in Figure 4. The pharmacokinetic measurements are summarised in Table 2. After cimetidine there was no significant change in the oral and intravenous half-life of labetalol, plasma clearance or the AUC of labetalol after intravenous dosing. The volume of distribution of labetalol was reduced. The AUC after the oral dose increased by 66%. The systemic bioavailability of labetalol was increased by 56%. The peak labetalol concentration increased from ng/ml (mean + s.e. mean) to ng/ml (2P < 0.05). The time to reach peak labetalol concentration wag unchanged. Supine heart rate and blood pressure were not significantly different following cimetidine pretreatment. Change in heart rate and blood pressure from baseline values showed an increased hypotensive response in the subjects as a whole (Figures 5 and 6). Table 1 Labetalol oral and intravenous pharmacokinetics before and after enzyme induction with glutethimide in five healthy subjects (mean + s.e. mean) Half-life Volume of Plasma AUC Systemic (min) distribution clearance (ng ml' min) bioavailability oral i. v. (1) (mllmin) oral i. v. (%) Before glutethimide 193 ± 19 8 ± ± ± ± ± ± 3 After glutethimide 176 ± ± ± ± ± ± ± 3 Significance (2P value) NS* NS NS NS 0.03 NS < * NS = not significant.

4 396 T. K. Daneshmend & C. J. C. Roberts 0-0) =ol C.2 10 j ),C,lo Figure 2 Mean (± s.e. mean) fall in supine systolic and diastolic BP and pulse rate in five healthy subjects following labetalol 0mg orally before (El) and after a 3 week course of glutethimide 500mg daily (-). 0)0 - l i subjects following 0 labetalol 0 0 mg/k 1 boralywegtiranosy 2 before (O) Time 3 and after a (h) 4 3 weeklttiie50m course o 5 6 Figure 2 Mean (± s.e. mean) fall in supine systolic and diastolic BP and pulse rate in five healthy E~ 10 0ofgltLbm1h S 0 0 1~~ ~~~~~~~~~~~~Tm h Fiur 3en(Oe en ali uiessoi n isoi Padplert nfv elh sujcsfloiglbtll05mgk2oywih0nrvnul,bfoe(l n fe ekcus ofguehmd 0mgdiy()

5 300 l Pre-cimetidine Labetalol and enzyme induction and inhibition Post-cimetidine S z E 4) a. Co Figure 4 Plasma labetalol concentrations (mean ± s.e. mean) in six healthy volunteers following administration of 0 mg orally (0) and 0.5 mg/kg body weight intravenously (0), before and after a 3 day course of cimetidine 1.6 g daily. One subject developed postural hypotension 3 h after the oral dose of labetalol following cimetidine pretreatment. The blood pressure dropped to 70/40 mm Hg and the subject felt lightheaded and almost fainted on standing. The blood pressure had not returned to baseline values 10 h later. This subject had the highest labetalol concentrations we have observed after a 0 mg oral dose in healthy adults. Plasma labetalol concentrations 1, 2, 3, 4, 5 and 6 h after the oral dose were 272, 135, 108, 86, 83 and 61 ng/ml in the basal state, and 25, 114, 470, 290, 312 and 246 ng/ml following cimetidine, respectively. Discussion This study shows that drugs such as glutethimide and cimetidine, which are known to cause microsomal oxidative enzyme induction and inhibition respectively, may also affect the metabolism of labetalol, a drug metabolised by Table 2 Labetalol oral and intravenous pharmacokinetics before and after enzyme inhibition with cimetidine in six healthy subjects (mean + s.e. mean) Half-life Volume of Plasma AUC Systemic (min) distribution clearance (ng ml' min) bioavailability oral i. v. () (mllmin) oral i. v. (%) Before cimetidine ± After cimetidine ± ± 8 Significance (2P value) NS* NS 0.04 NS 0.06 NS 0.06 * NS = not significant.

6 398 T. K. Daneshmend & C. J. C. Roberts E -10 Co co XE~~1~0 D On 2L0 1J 10 OcT l-e Figure 5 Mean (± s.e. mean) fall in supine systolic and diastolic BP and pulse rate in six healthy subjects following labetalol 0 mg orally before (O) and after a 3 day course of cimetidine 1.6 g daily (-). glucuronidation. Drugs which modify micro- mg per day was shown to increase mean somal oxidative enzyme activity may be asso- indocyanine green clearance by 15% and anticiated with changes in liver blood flow (Ohnhaus pyrine clearance by 90% (Roberts et al., 1976). et al., 1971; Branch et al., 1974; Feely et al., n contrast a three week course of glutethimide 1981). A 3 week course of phenobarbitone mg per day resulted in a 55% increase in 0..Y 0) l lu 0)_1 F : U U, - en 0. - CL~~~. 2 C Figure 6 Mean (± s.e. mean) fall in supine systolic and diastolic BP and pulse rate in six healthy subjects following labetalol 0.5 mg/kg body weight intravenously before (OJ) and after a 3 day course of cimetidine 1.6 g daily (U).

7 Labetalol and enzyme induction and inhibition 399 mean antipyrine clearance, but a 17% reduction in mean indocyanine green clearance action between cimetidine and morphine was benzodiazepines. A potentially lethal inter- (Jackson et al., 1978). We therefore chose observed by Fine & Churchill (1981). n addition, cimetidine appears to inhibit morphine glutethimide as the enzyme inducing agent in this study so as to minimise the concomitant rise conjugation by rat hepatic tissue in vitro (Mojaverian et al., 1981). Morphine, like in liver blood flow seen with other enzyme labetalol, inducing agents. Cimetidine, in addition to its action of inhibiting microsomal oxidative enzymes, is thought to reduce liver blood flow in man (Feely et al., 1981). However we found no change in indocyanine green kinetics in ten subjects given cimetidine 1 g/day for 4 weeks (Daneshmend et al., 1984). n the present study, pretreatment with glutethimide and cimetidine did not result in a change in labetalol CL or t½1 after the intravenous dose. This implies that liver blood flow was unchanged and that the changes in bioavailability were not due to alterations in liver blood flow. Our studies suggest that the changes in bioavailability of labetalol are due to glutethimide and cimetidine related alterations in the first pass glucuronidation of labetalol. These conclusions do not, however, accord with the recognised effects of cimetidine and glutethimide. The mechanism of cimetidine associated enzyme inhibition is thought to be ligand binding of the imidazole group to the oxygen binding site of cytochrome P-450, and also to the substrate binding sites. On this basis impairment of phase metabolic reactions has been predicted, with sparing of cytochrome P- 450 independent phase reactions such as glucuronidation. A similar inference is drawn from the inhibition of cimetidine of the oxidation of diazepam and desmethyldiazepam, but not the glucuronide conjugation of lorazepam and oxazepam (Patwardhan et al., 1980; Klotz & Reimann, 1980). t is possible, though, that cimetidine inhibits the glucuronidation of compounds other than References is a high clearance drug which is metabolised by glucuronide conjugation (Patwardhan et al., 1981). Therefore in the present study cimetidine may have caused inhibition of the presystemic glucuronidation of labetalol, resulting in increased bioavailability. The molecular interaction between glutethimide and microsomal oxidative enzymes is less well defined. Most enzyme inducing agents cause an increase in the smooth endoplasmic reticulum and an increase in the quantity of oxidative enzymes. Whether there is a concomitant rise in the level of glucuronide conjugation enzymes is unknown. On the basis of the venous equilibration model of hepatic elimination (Rowland et al., 1973; Wilkinson & Shand, 1975), liver blood flow is the major determinant of the elimination of high clearance drugs (i.e., drugs with a high hepatic extraction ratio) when given intravenously, while the activity of drug metabolising enzymes is the major determinant of clearance when these drugs are given orally. Thus the absence of a cimetidine or glutethimide associated change in the pharmacokinetics of labetalol given intravenously suggests that neither drug caused a change in liver blood flow. The mechanism for the change in bioavailability is thus likely to be a change in the activity of drug metabolising enzymes. n conclusion, the demonstration of altered labetalol bioavailability after oral dosing, without a change in the kinetics after the intravenous dose, suggests that glutethimide and cimetidine may influence phase conjugation reactions in addition to their better known effects on phase reactions. Branch, R. A., Shand, D. G., Wilkinson, G. R. & Nies, A. S. (1974). ncreased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. J. clin. nvest., 53, Daneshmend, T. K., Ene, M. D., Parker, G. & Roberts, C. J. C. (1984). The effects of chronic cimetidine on apparent liver blood flow and hepatic microsomal enzyme activity. Gut, 25, Desmond, P. V., Shaw, R. G., Bury, R. W., Mashford, M. L. & Breen, K. J. (1981). Cimetidine impairs the clearance of an orally administered high clearance drug, chlormethia zole. Gastroenterology, 80, Feely, J., Wilkinson, G. R. & Wood, A. J. J. (1981). Reduction of liver blood flow and propranolol metabolism by cimetidine. New Engl. J. Med., 394, Fine, A. & Churchill, D. N. (1981). Potentially lethal interaction of cimetidine and morphine. Can. med. Ass. J., 124, Heagerty, A. M., Donovan, M. A., Castleden, C. M., Pohl, J. F., Patel, L. & Hedges, A. (1981). nfluence of cimetidine on pharmacokinetics of propranolol. Br. med. J., 282, Homeida, M., Jackson, L. & Roberts, C. J. C. (1978) Decreased first pass metabolism of labetalol in chronic liver disease. Br. med. J., 2, Jackson, L., Homeida, M. & Roberts, C. J. C.

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