Summary
The purpose of this study was to examine the influence of cigarette smoking and gender on the pharmacokinetics of metoprolol.
Eighteen volunteers with no evidence of clinical disease each randomly received the following doses of metoprolol tartrate: 100 mg orally, 200 mg orally and 20 mg as a constant-rate intravenous infusion over 20 min.
The only significant difference between smokers (S) and nonsmokers (NS) was that S had a larger steady-state volume of distribution (3.3 vs 2.5 l/kg). There were no differences in half-life, systemic clearance or bioavailability (f). No differences were observed between males (M) and females (FM) for any of the kinetic parameters examined. Systemic bioavailability varied markedly between subjects (range: 15 to 92%). In fifteen of the eighteen subjects, f was higher after the 200-mg dose compared to the 100-mg dose.
These results suggest that metoprolol may be subject to saturable presystemic elimination and extend the previous observations of Johnsson et al. [1] who showed that f increased from 31% to 46% when doses were increased from 20 to 100 mg. However, the difference in f as the dose is increased is unlikely to be clinically significant since the mean difference is smaller than the variation in f among subjects.
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References
Johnsson G, Regardh CG, Sorvell L (1975) Combined pharmacokinetic and pharmacodynamic studies in man of the adrenergic β-receptor antagonist metoprolol. Acta Pharmacol Toxicol 36 [Suppl 5]: 31–44
Jack D, Quarterman C, Zaman R, Kendall M (1982) Variability of beta-blocker pharmacokinetics in young volunteers. Eur J Clin Pharmacol 23: 37–42
Vesell E (1982) On the significance of host factors that affect drug disposition. Clin Pharmacol Ther 31: 1–7
Wilson K (1984) Sex-related differences in drug disposition in man. Clin Pharmacol 9: 189–202
Giudicelli J, Tillement J (1977) Influence of sex on drug kinetics in man. Clin Pharmacokinet 2: 157–166
Proksch R, Lamy P (1977) Sex variation and drug therapy. Drug Intell Clin Pharm 11: 398–406
Kato R (1974) Sex-related differences in drug metabolism. Drug Metab Rev 3: 1–32
Jusko W (1978) Role of tobacco smoking in pharmacokinetics. J Pharmacokinet Biopharm 6: 7–39
Jusko W (1979) Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev 9: 221–236
Jusko W (1984) Smoking effects in pharmacokinetics. In: Benet L, Massoud N, Gambertoglio J (eds), Pharmacokinetic basis for drug treatment. Raven Press, New York
Jick H (1974) Smoking and clinical drug effects. Med Clin N Am 58: 1143–1149
US Department of Health, Education and Welfare (1979) Smoking and health: A report of the surgeon general. DHEW Publication No. (PHS) 79-50066, Washington, DC
Dawson G, Vestal R (1982) Smoking and drug metabolism. Pharmacol Ther 15: 207–221
Yamaoka K, Nakagawa T, Uno T (1978) Statistical moments in pharmacokinetics. J Pharmacokinet Biopharm 6: 547–558
Benet L, Galeazzi R (1979) Noncompartmental determination of the steady-state volume of distribution. J Pharm Sci 68: 1071–1074
Perrier D, Mayersohn M (1982) Noncompartmental determination of the steady-state volume of distribution for any mode of administration. J Pharm Sci 71: 372–373
Kim K, Kohout F (1975) Analyses of variance and covariance: Subprograms ANOVA and ONEWAY. In: Nie N, Hull C, Steinbrenner K, Bent D (eds) Statistical package for the social sciences (SPSS). Mc Graw-Hill, New York
Winer B (62) Statistical principles in experimental design. McGraw-Hill, New York, pp 298–378
Jennrich R, Sampson P, Frane J (1981) P2V Analysis of variance and covariance including repeated measures. In: Dixon W, Brown M, Engelman L, Frane J, Hill M, Jennrich R, Toporek J (eds) BMDP statistical software. University of California Press, Berkeley, CA
Lam F, Hung C, Perrier D (1985) Estimation of variance for harmonic mean half-lives. J Pharm Sci 74: 229–231
Wilkinson G, Shand D (1975) A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 18: 377–390
Regardh C, Borg K, Johansson R, Johnsson G, Palmer L (1974) Pharmacokinetic studies on the selective β1-receptor antagonist metoprolol in man. J Pharmacokinet Biopharm 2: 347–364
Hitzenberger G, Fitscha P, Beveridge T, Nuesch E, Pacha W (1982) Effects of age and smoking on the pharmacokinetics of pindolol and propranolol. Br J Clin Pharmacol 13: 217S-222S
Vestal R, Wood A, Branch R, Shand D, Wilkinson G (1979) Effects of age and cigarette smoking on the disposition of propranolol in man. Clin Pharmacol Ther 26: 8–15
Gardner S, Cady W, Ong Y (1980) Effect of smoking on the elimination of propranolol hydrochloride. Int J Clin Pharmacol Ther Toxicol 18: 421–424
Barrett A, Collum V (1968) The biological properties of the optical isomers of propranolol and their effects on cardiac arrhythmias. Br J Pharmacol 34: 43–55
Regardh C, Johnsson G, Jordo L, Lundborg P, Persson B, Ronn O (1980) Plasma concentrations and beta-blocking effects in normal volunteers after intravenous doses of metoprolol and propranolol. J Cardiovasc Pharmacol 2: 715–723
Parving H (1972) The effect of hypoxia and carbon monoxide exposure on plasma volume and capillary permeability to albumin. Scand J Clin Lab Invest 30: 49–56
Jordo L, Attman P, Aurell M, Johansson L, Johnsson G, Regardh C (1980) Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function. Clin Pharmakokinet 5: 169–180
Shand D, Rangano R (1972) The disposition of propranolol I: Elimination during oral absorption in man. Pharmacology 7: 159–168
Gomeni R, Bianchetti G, Sega R, Morselli P (1977) Pharmacokinetics of propranolol in normal healthy volunteers. J Pharmacokinet Bipharm 5: 183–192
Mackichan J, Pyszczynski D, Jusko W (1980) Dose-dependent disposition of oral propranolol in normal subjects. Biopharm Drug Dispos 1: 159–166
Wargin W, Sawchuk R, McBride J, McCoy H, Rylander M (1982) Variable first-pass elimination of propranolol following single and multiple oral doses in hypertensive patients. Eur J Drug Metab Pharmacokinet 7: 183–189
Vesell E (1982) On the significance of host factors that affect drug disposition. Clin Pharmacol Ther 31: 1–7
Lennard M, Tucker G, Woods H (1986) The polymorphic oxidation of β-adrenoceptor antagonists. Clinical pharmacokinetic considerations. Clin Pharmacokinet 11: 1–17
Lennard M, Silas J, Freestone S, Ramsay L, Tucker G, Wood H (1982) Oxidation phenotype — a major determinant of metoprolol metabolism and response. N Eng J Med 307: 1558–1560
Lennard M, Silas J, Freestone S, Tucker G, Ramsay L, Woods H (1983) Impaired metabolism of metoprolol in poor hydroxylators of debrisoquine. Drugs 25 [Suppl 2]: 147–148
Lennard M, Tucker G, Silas M, Freestone S, Ramsay L, Woods L (1983) Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquine metabolizers. Clin Pharmacol Ther 34: 732–734
Lennard M, Silas J, Freestone S, Trevethick J (1982) Defective metabolism of metoprolol in poor hydroxylators of debrisoquine. Br J Clin Pharmacol 14: 301–303
Lennard M, Freestone S, Ramsay L, Tucker G, Woods H (1983) Oxidation phenotype and beta-blockers. N Eng J Med 308: 965
Shah R, Oates N, Idle J, Smith R (1982) Beta-blockers and drug oxidation status. Lancet 1: 508–509
Lennard M, Tucker G, Silas J, Woods H (1986) Debrisoquine oxidation phenotype and metabolism and action of metoprolol, timolol, propranolol and atenolol. Xenobiotica 15: 435–447
Dayer P, Leemann T, Marmy A, Rosenthaler J (1985) Interindividual variation of beta-adrenoceptor blocking drugs, plasma concentration and effect: influence of genetic status on behavior of atenolol, bopindolol and metoprolol. Eur J Clin Pharmacol 28: 317–320
McGourty J, Silas J, Lennard M, Tucker G, Woods H (1985) Metoprolol metabolism and debrisoquine polymorphism — population and family studies. Br J Clin Pharmacol 20: 555–566
Briant R, Dorington R, Ferry D, Paxton J (1983) Bioavailability of metoprolol in young adults and the elderly, with additional studies on the effects of metoclopramide and probanthine. Eur J Clin Pharmacol 25: 353–356
Kendall M, Brown D, Yates R (1977) Plasma metoprolol concentrations in young, old and hypertensive subjects Br J Clin Pharmacol 4: 497–499
Regardh C, Landahl S, Larsson M, Lundborg P, Steen B, Hoffmann K, Lagerstrom P (1983) Pharmacokinetics of metoprolol and its metabolite α-OH-metoprolol in healthy, non-smoking, elderly individuals. Eur J Clin Pharmacol 24: 221–226
Quarterman C, Kendall M, Jack D (1981) The effect of age on the pharmacokinetics of metoprolol and its metabolites. Br J Clin Pharmacol 11: 287–294
Larsson M, Landahl S, Lundbog P, Regardh C (1984) Pharmacokinetics of metoprolol in healthy, elderly, non-smoking individuals after a single dose and two weeks of treatment. Eur J Clin Pharmacol 27: 217–222
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Schaaf, L.J., Campbell, S.C., Mayersohn, M.B. et al. Influence of smoking and gender on the disposition kinetics of metoprolol. Eur J Clin Pharmacol 33, 355–361 (1987). https://doi.org/10.1007/BF00637630
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DOI: https://doi.org/10.1007/BF00637630