Introduction. Feely et al. 11 as well as Heagerty et al. [21 have shown that concurrent administration of cimetidine impairs the elimination of propranolol.
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Clinical Science (1982) 63.45 ls-453~
Interaction of metoprolol, propranolol and atenolol with cimetidine
W. K I R C H * , H . S P A H N t , H. K t ) H L E R * A N D E. M U T S C H L E R t * I Medizinische Uniuersitatsklinik Mainz. tPharmakologisches Institut fur Naturwissenschaftler der Uniuersitat FrankfurtlM. FRG
Summary 1. Pharmacokinetics of metoprolol, propranolol and atenolol were investigated in six healthy volunteers after 7 days of oral monotherapy with these drugs and after 7 days concurrent administration, with each of these /3-adrenoceptor antagonists with cimetidine. 2. Cimetidine did not interact with atenolol, whereas mean peak plasma concentrations of metoprolol were increased by 7096, and those of propranolol by 95% with concurrent administration of cimetidine (P < 0.05). 3. The area under the plasma concentrationtime curve for propranolol and metoprolol was similarly increased (P < 0.05).
Key words: atenolol, cimetidine, drug interaction, metoprolol, propranolol. Introduction Feely et al. 11 as well as Heagerty et al. [21 have shown that concurrent administration of cimetidine impairs the elimination of propranolol and increases its plasma levels considerably. The aim of the present study was to determine the degree of increase of the plasma propranolol levels induced by cimetidine application after chronic therapy with these two substances and to compare it with the influence of cimetidine on metoprolol and atenolol kinetics. Patients and methods
Six healthy male volunteers were investigated (mean age 23.6 f 1.9 years; range 22-31 years; mean body weight 68.7 f 5.1 kg; X f SEM). All Correspondence: Dr Dr med. W. Kirch, I Medizinische Klinik und Poiiklinik, der Johannes Gutenberg-Universitat, Langenbeckstrasse 1, D 6500 Mainz 1, FRG.
were non-smokers and had no evidence of kidney, liver, respiratory, cardiovascular or thyroid disease and they had given their informed consent to participate in the study. No concomitant therapy was taken. During the course of the study, each subject acted as his own control in a simple cross-over design. Propranolol (80 mg twice daily) was first given orally to the volunteers for 6 days as monotherapy. During chronic treatment with the D-adrenoceptor antagonist, plasma samples were taken before the morning dose and 4 h afterwards. After the last oral dose of propranolol (80 mg) on the morning of the seventh day blood specimens were obtained at appropriate intervals up to 24 h after ingestion of the drug. Immediately afterwards, when propranolol levels could no longer be measured, propranolol(80 mg twice daily) together with cimetidine (200 mg thrice daily, and 400 mg at night) were administered orally for 6 days. Plasma samples were obtained before the morning doses and 4 h afterwards during the chronic combination therapy. On the morning of the seventh day of treatment the last oral doses of propranolol (80 mg) and cimetidine (200 mg) were given and blood specimens were taken up to 48 h for measurement of propranolol concentrations. Measurement of blood pressure and pulse frequency were @ways performed at the same time that blood samples were taken. After a therapyfree interval of 2 weeks, the same procedure was performed in the same volunteers for metoprolol (100 mg twice daily as monotherapy and metoprolol 100 mg twice daily combined with cimetidine, 200 mg thrice daily and 400 mg at night) as well as for atenolol (100 mg once a day as monotherapy and combined with cimetidine, 200 mg thrice daily and 400 mg at night). Propranolol, metoprolol and atenolol were determined in plasma and urine by measuring the intrinsic fluorescence of these drugs on thin-layer
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W. Kirch et al.
chromatograms 13-51. The degree of P-adrenoceptor blockade produced by monotherapy with the drugs as well as by the combination therapy with cimetidine was measured by the inhibition of exercise-induced tachycardia. Statistical evaluation included the Wilcoxon matched pairs signed rank test. Values are expressed as means ? SEM.
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Results
Interaction of propranolol with cimetidine
Time to reach mean peak plasma concentrations (fmax,) was about 2 h after the ultimate oral dose on day 7 of propranolol monotherapy as well as of combined treatment of propranolol and cimetidine. Peak plasma concentrations (CmaX,) averaged 125.9 ng/ml in monotherapy and increased to 250.8 ng/ml after concurrent administration of cimetidine. The area under the plasma concentration-time curve (AUC), which increased more than double (21 12.0 ng h-' ml-' after combination therapy compared with 941.6 ng h-' ml-' with propranolol alone) behaved similarly (P < 0.05). The elimination half-life of propranolol ( t t ) tended to be prolonged when cimetidine was administered concurrently (7.57 h), whereas it was calculated as 5 - 5 8 h after monotherapy, but the difference was not statistically significant. Interaction of metoprolol with cimetidine
Mean peak plasma concentrations (Cmax,) of metoprolol increased from 177.2 ng/ml under monotherapy to 283.8 ng/ml when cimetidine was administered concurrently (P < 0.05; Fig. 1). The AUC for metoprolol rose from 1167.0 ng h-' ml-' when metoprolol was used alone to 1885.1 ng h-' ml-' with combination treatment (P < 0.05). The considerable increase of plasma metoprolol levels when cimetidine was coadministered could be observed from day 1 of treatment, onwards throughout the whole therapy period. The elimination half-life was prolonged to 6.97 h in combination therapy compared with 4.35 h after monotherapy with metoprolol. Interaction of atenolol with cimetidine
None of the kinetic parameters of atenolol were distinctly altered by the concurrent administration of cimetidine. Maximum plasma concentrations were calculated as about 6 10-660 ng/ml, elimination half-life was close to 7.5 h, urinary recovery ranged between 40% and 50%
Time (h)
FIG. 1. Mean plasma levels after the last oral dose of metoprolol (100 mg) as monotherapy and after combination with cimetidine (200 mg) on the seventh day of the chronic application: A-A, metoprolol metoprolol + cimetidine. monotherapy;
.---+,
and renal clearance was between 120 and 145 mllmin. Clinical significance
The results of the present study confirm the kinetic interaction of propranolol with cimetidine found by other groups 11, 21. In elderly patients, possibly in those with a sick sinus syndrome, adverse effects due to the higher propranolol levels might occur. Such a case has been described (11. In the present study it could be shown for the first time that metoprolol also interacts considerably with cimetidine. This might have been expected because metoprolol is metabolized by the liver nearly to the same extent as propranolol. The pharmacokinetics of atenolol, a hydrophilic P-adrenoceptor antagonist chiefly excreted by the kidneys, could have been expected not to be altered by concomitant cimetidine application. This assumption has been confirmed by the results of the present study, in which the kinetic behaviour of atenolol calculated from chronic monotherapy and from chronic combined treatment with cimetidine parallels that which was described by several other authors [6,71. Since cimetidine has in the meantime become one of the most often used drugs in the world, the possibility of interaction with /?-adrenoceptor antagonists, which are also frequently administered, has to be taken in consideration in order to avoid side effects of substances such as propranolol or metoprolol. Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft and the Dr Robert
Cimetidine and 8-adrenoceptor antagonists
Pfleger Stiftung, Bamberg, FRG. We are grateful to Mrs Silke Podkowik and to Mrs Susanne Cattarius-Korb for their excellent technical assistance.
References 1 II FEELY.J.. WILKINSON.C.R. & WOOD. A.R. (1980) Cimetidine administration results in increased effects of propranolol and higher propranolol levels. Circululion, 62, Abstract 982. M.A.. CASTLEDEN.C.M.. POHL. I21 HEACERTY.A.M., DONOVAN. J.F., PATEL, L. & HEDGES, A. (1981) Influence ofcimetidineon pharmacokinetics of propranolol. British Medical Journul. 282, 19 17- 19 19.
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131 SCHAFI:H.M.. G ~ I S L ~ H.E. H , & MUTSLIILI.H. t. (1977) Fluorimetric determination of propranolol and N-de\i\opropyl propranolol in plasma by direct evaluation of thin-layer chromatograms. Journul of Chromurrigruphy. 143,607-6 10. 141 SCIIAFER. M. & MUTSLtiL€.R. E. (1979) Fluorimetric determination of oxprenolol and metoprolol in plasma by direct evaluation of thin-layer chromatograms. Jriurnul of C h m m u n gruphy. 64,247-252. 151 S C H A F ~ RM. . & MUTSCHLER. E. (1979) Fluorimetric determination of atenolol in plasma and urine by direct evaluation of thin~layer chromatograms. Journul of Chromutogruphy. 169, 477-48 I, 161 KtHCtI. W.. KiitIl.tH. H.. M U T S C H L t R . E. & SCIIAPW M. (1981) Pharmacokinetic5 of atenolol in relation to renal function. Europeun Journul of Clinical Phurmucolrigy. 19. 65-82. W.D.. WtNER. H.. KocHAK.G..CCJH~.~. 1. & VtLl.. R. 171 MASON. (1979) Kinetics and absolute bioavailability of atenolol. Clinicul Phurmucology and Therupeutio. 25,408-4 15.
