Pharmacokinetic and pharmacodynamic interactions between phenprocoumon and atenolol or metoprolol

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1 Br. J. clin. Pharmac. (1984), 17, 97S-12S Pharmacokinetic and pharmacodynamic interactions between phenprocoumon and atenolol or metoprolol H. SPAHN', W. KIRCH2,. MUTSCHLR',.. OHNHAUS2, N. R. KITFRINGHAM2, H. J. LOGRING2 & D. PAAR2 'Pharmakologisches Institut fur Naturwissenschaftler, Johann Wolfgang Goethe-Universat, Theodor-Stern-Kai 7, Gebaude 75A, D-6 Frankfurt/Main 7 and 2Universitatsklinikum der Gesamthochschule ssen, Hufelandstrasse 55, D-43 ssen 1, West Germany Pharmacological interactions in both directions between phenprocoumon and atenolol and metoprolol were investigated using a crossover trial. Co-administration of phenprocoumon did not significantly affect Cmax, tmax, ti,2,22, AUC for atenolol or metoprolol. Co-administration of metoprolol, but not atenolol, increased mean plasma phenprocoumon concentrations 4 and 6 h after dosing and was caused by a decrease in the apparent volume of distribution. This increase in plasma phenprocoumon was not associated with an increase in prothrombin time or in the total area under the concentration-time curve. Although the transient increase of phenprocoumon plasma levels caused by metoprolol may be of little clinical significance after a single dose of phenprocoumon, a more important alteration in phenprocoumon disposition and effect should be considered in individual patients on long-term therapy. Keywords atenolol lipophilicity metoprolol pharmacokinetics phenprocoumon Introduction Coumarin anticoagulants have been found to effect of phenprocoumon on the pharmacokinetic parameters of single dose administration of interact with many other drugs (Koch-Weser & Sellers, 1971). The kinetics and action of highly the /8-adrenoceptor blocking agents atenolol protein-bound coumarin anticoagulants may be (hydrophilic) which is eliminated almost entirely modified by concomitantly administered drugs. by the kidneys (Brown et al., 1976) and metoprolol (lipophilic) which is eliminated mainly Because of their small therapeutic range these effects form some of the most important inter-' by hepatic metabolism; and (b) to consider the, actions in drug therapy. In addition, anticoagulants are known to affect the action of other the /8-adrenoceptor blockers on the pharmaco- influence of the physico-chemical properties of drugs (Ammon, 1981). The oral anticoagulant kinetics and anticoagulant activity of phenprocoumon in view of the difference in the metabo- drug phenprocoumon is widely used in continental urope for treatment of thromboembolic lism of phenprocoumon compared with warfarin. disorders. Although it is structurally similar to warfarin, the metabolism of phenprocoumon and warfarin involves different pathways, phenprocoumon being principally eliminated by onestep conjugation (Heni et al., 1976) whereas Methods warfarin undergoes extensive oxidation (Lewis The study was performed on a group of six healthy & Trager, 197). volunteers aged 2-25 years (mean age 22.5 The study was designed: (a) to investigate the years; 5 M, 1 F; mean body weight 71.1 kg). 97S

2 98S H. Spahn et al. ffect ofphenprocoumon on /3-adrenoceptor blocker pharmacokinetics In the study, each person acted as his own control, and intra-individual comparisons were performed. In the first two trial periods atenolol (A) 1 mg and metoprolol (M) 1 mg were administered orally to the volunteers. Using the same volunteers the investigation was repeated with atenolol plus phenprocoumon 15 mg (A + P) and metoprolol plus phenprocoumon (M + P). Plasma samples were taken before and 1, 2, 3, 4, 6, 12 and 24 h after administration in order to determine /3-adrenoceptor-antagonist concentrations. Urine was collected for 24 h after drug intake. Plasma and urinary concentrations of atenolol and metoprolol were determined using fluorodensitometry (Schafer & Mutschler, 1979a, b). The terminal half-lives (t½,x) were calculated by linear regression analysis including the values of the terminal log-linear phase. AUC values were calculated according to the trapezoidal rule (-24 h) and renal clearance was determined from the amounts of drug excreted in urine (Ae) from to 24 h. Statistical evaluations were carried out using the Wilcoxon test for paired differences (P >.5 = NS). ffect ofatenolol and metoprolol on anticoagulant pharmacology Initially each subject received a single dose (15 mg) of phenprocoumon (P) alone and subsequently, following a drug-free period of 4 weeks, the same dose was repeated with the concurrent administration of a single dose of either atenolol 1 mg (P + A) or metoprolol 1 mg (P + M). Finally, after a second drug-free 4-week interval, each subject received a third dose of phenprocoumon along with the other f3-adrenoceptor blocker. All drugs were given orally as conventional commercial preparations, at 9. h following an overnight fast. Concentrations of phenprocoumon were determined using h.p.l.c. with spectrophotometric detection following extraction from acidified plasma samples with N-hexane. [3H]- phenprocoumon (approximately 1 nci) was added to each sample prior to extraction. fficiency of extraction was quantified by liquid scintillation counting of the h.p.l.c. eluent corresponding to the phenprocoumon peak. Plasma concentration-time data were analysed by nonlinear regression according to a one-compartment open model. The anticoagulant activity of phenprocoumon was quantified by measuring prothrombin times (Quick test and partial prothrombin time) on four occasions after dosing. Statistical comparisons of the data were performed using Student's t-test for paired data. Results ffect ofphenprocoumon on /3-adrenoceptor blocker pharmacokinetics Mean plasma levels of atenolol and metoprolol with and without phenprocoumon are shown in Figures 1 and 2 and mean pharmacokinetic parameters are given in Table 1. Mean peak plasma atenolol concentration was lower (NS) after co-administration of phenprocoumon (593 ng/ml) than without addition of the anticoagulant (793 ng/ml). Similarly the 1l, C 1 1IV I 1L S Figure 1 Mean plasma levels of atenolol after administration of 1 mg atenolol with () and without () phenprocoumon (n = 6).

3 Short Report 99S.S.5. ) I I Figure 2 Mean plasma levels of metoprolol after administration of 1 mg metoprolol with () and without (*) phenprocoumon (n = 6). mean AUC for A + P (446 ng ml- 'h) was lower (NS) than for A (5753 ng ml-' h). The time to peak plasma atenolol concentration (tmax) was less (NS) for A + P (1.3 h) than for A (3. h). The peak plasma metoprolol concentration was also lower (NS) after co-administration of phenprocoumon (133 ng/ml) than without the anticoagulant (236 ng/ml). Furthermore the AUC was lower (NS) for M + P (881 ng ml-l h) than for M (127 ng ml-' h). The mean half-life of metoprolol was slightly greater (NS) after additional administration of phenprocoumon. ffect ofatenolol and metoprolol on anticoagulant pharmacology The mean plasma concentrations of phenprocoumon, when given alone or concurrently with atenolol or metoprolol, are shown in Figures 3 and 4. Significant differences in the plasma concentrations were seen 4 and 6 h following phenprocoumon plus metoprolol co-administration. Atenolol had no effect on the mean plasma concentrations of phenprocoumon at any time point. The areas under the concentration-time curves (AUC) varied little for each individual within the three treatment phases; the mean values being remarkably similar in all three cases (Table 2). In contrast, the apparent volume of distribution (Vd) was smaller in every subject following metoprolol and the mean Vd for the metoprolol treatment was significantly lower than for phenprocoumon alone (P <.5). Atenolol, however, had no statistically significant effect on Vd. The mean half-life (t½) of phenprocoumon was numerically lower after both atenolol and metoprolol co-administration although the difference was only statistically significant with metoprolol (Table 3). Neither atenolol nor metoprolol altered the total body clearance of phenprocoumon. Prothrombin times showed large inter-individual variability but there were no statistical differences between the three different treatments. Table 1 Pharmacokinetic parameters for atenolol and metoprolol during different treatment periods (mean ± s.e mean). Atenolol Atenolol Metoprolol Metoprolol + phenprocoumon + phenprocoumon Cmax (ng/ml) ± ± tmax (h) 3. ± ± ± ±.2 ty/2.xz (h) AUCO24h (ngml- Ih) ± ± ± 34.6 AeO24h (mg) CLren (ml/min) 56.4 ± ± 12.5

4 loos H. Spahn et al C C ) [ ntj. I m I II I I I I I Fiure 3 Plasma concentrations of phenprocoumon in six healthy volunteers following oral administration ofphenprocoumon 15 mg alone (-) or concurrently with atenolol 1 mg (A). ach point represents the mean ± s.e. mean o L-.75 CL 1.25_.5 2.r-.25- I I I I ( Figure 4 Plasma concentrations of phenprocoumon in six healthy volunteers following oral administration of phenprocoumon 15 mg alone (@) or concurrently with metoprolol 1 mg (A). ach point represents the mean + s.e. mean.

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6 12S H. Spahn et al. Discussion The degree of interaction of atenolol and metoprolol on the coumarins can be predicted on the basis of the albumin binding of these,3-adrenoceptor blockers. Since the extent of plasma protein binding is known to be low for the investigated /8-adrenoceptor blockers, we did not expect to find an interaction caused by competition for albumin binding sites; indeed the results do not indicate such an interaction. Furthermore, other pharmacokinetic interactions, due to enzyme blockade or enzyme induction, were not apparent in this study. The decrease in apparent volume of distribution of phenprocoumon following metoprolol co-administration caused a transient increase in phenprocoumon concentrations at the time corresponding to the peak levels. However, the increase in elimination rate resulted in unchanged total AUC_c> and probably explains why no effect on prothrombin time was observed since this parameter was first measured 24 h after dosing by which time the plasma levels were no References Ammon, H. P. T. (1981). Arzneimittelneben-undwechselwirkungen, Wissenschaftliche Verlagsgesellschaft mbh Stuttgart. Brown, H. C. et al. (1976). Clinical pharmacologic observations on atenolol, a beta-adrenoceptor blocker. Clin. Pharmac. Ther., 2, Heni, G., Lenhart, G. & Glogner, P. (1976). liminations-kinetik von Phenprocoumon (Marcumar ) bei Leberzirrhose und Vorbehandlung mit Phenobarbital. Int. J. clin. Pharmac., 13, 4, Koch-Weser, J. & Sellers,. M. (1971). Drug Interactions with Coumarin Anticoagulants. New ngl. J. Med., 1, and longer significantly different from control values. Nevertheless, the possibility of altered anticoagulant activity, particularly in patients undergoing long-term therapy, should be considered if metoprolol is to be given in combination with phenprocoumon. The explanation of this interaction is unclear but may involve the displacement of phenprocoumon from tissue binding sites, possibly within the liver itself, where phenprocoumon exerts its pharmacological effect and where concentrations of both drugs might be expected to be relatively high a short time after dosing. A decrease in phenprocoumon concentrations outside the circulatory system would also explain why no increase in prothrombin time was observed. The lack of any interactions between atenolol and phenprocoumon suggests that f-adrenoceptor blockers of the hydrophilic type are less likely to interfere with anticoagulant therapy. The authors are grateful to Mrs S. Cattarius-Korb for her excellent technical assistance. Lewis, R. J. & Trager, W. F. (197). Warfarin metabolism in man: Identification of metabolites in urine. J. clin. Invest., 49, Schafer, M. & Mutschler,. (1979a). Fluorimetric determination of oxprenolol in plasma by direct evaluation of thin-layer chromatograms. J. Chromatog., 64, Schafer, M. & Mutschler,. (1979b). Fluorimetric determination of atenolol in plasma and urine by direct evaluation of thin-layer chromatograms. J. Chromatog., 169,