Abstract
Seven healthy volunteers showing a fourteenfold range in steady-state plasma concentrations on oral alprenolol (200 mg b.i.d.) were investigated by administration of 5 mg of the drug intravenously and then 50, 100, 150, and 200 mg as single oral doses. The rank order for individual steady-state plasma concentrations was the same as that for the relative bioavailability of the 200 mg dose. The area under the plasma concentration-time curve showed a nonlinear increase with the dose. As the relative availability was a good predictor of steady state while clearance after intravenous administration was not, it was concluded that differences in first-pass elimination markedly contribute to the interindividual variability in steady state plasma concentrations. After pentobarbital treatment, the area under the plasma concentration curve of the 200 mg dose was decreased to 32% and 59% of the pretreatment values in two subjects, but there was no change in the plasma half-life of alprenolol. This indicates induction of the first-pass extraction of alprenolol in man.
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References
D. G. Shand, M. S. Nuckolls, and J. A. Oates. Plasma propranolol levels in adults with observations in four children.Clin. Pharmacol. Ther. 11:112–120 (1970).
M. D. Rawlins, P. Collste, M. Frisk-Holmberg, M. Lind, J. Östman, and F. Sjöqvist. Steady-state plasma concentrations of alprenolol in man.Eur. J. Clin. Pharmacol. 7:353–356 (1974).
P. A. Harris and S. Riegelman. Influence of the route of administration on the area under the plasma concentration time curve.J. Pharm. Sci. 58:71–75 (1969).
M. Gibaldi, R. N. Boyes, and S. Feldman. Influence of first pass effect on availability of drugs on oral administration.J. Pharm. Sci 60:1338–1340 (1971).
M. Rowland. Influence of route of administration on drug availability.J. Pharm. Sci. 61:70–74 (1972).
W. H. Barr. Factors involved in the assessment of systemic or biologic availability of drug products. In Symposium on Formulation Factors Affecting Therapeutic Performance of Drug Products, Washington, D.C., April 1969. DrugInform. Bull. 3:277–345 (1969).
D. G. Shand and R. E. Rangno. The disposition of propranolol.Pharmacology 7:159–168 (1972).
B. Åblad, M. Ervik, J. Hallgren, G. Johnsson, and L. Sölvell. Pharmacological effects and serum levels of orally administered alprenolol in man.Eur. J. Clin. Pharmacol. 5:44–52 (1972).
G. H. Evans and D. G. Shand. Disposition of propranolol. V. Drug accumulation and steady-state concentrations during chronic oral administration in man.Clin. Pharmacol. Ther. 14:427–493 (1973).
C. von Bahr, G. Alván, M. Lind, B. Mellström, and F. Sjöqvist. “First pass” effect and dose dependent availability as factors contributing to interindividual differences in equilibrium concentrations of alprenolol in man.Acta Pharm. Suec. 11:649–650 (1974).
G. Alván, O. Borgå, M. Lind, L. Palmér, and B. Siwers. First pass hydroxylation of nortriptyline: Concentrations of parent drug and major metabolites in plasma.Eur. J. Clin. Pharmacol. (in press).
S. Riegelman. Physiological and pharmacokinetic complexities in bioavailability testing.Pharmacology 8:118–141 (1972).
R. Grundin, P. Moldéus, S. Orrenius, K. O. Borg, I. Skånberg, and C. von Bahr. The possible role of cytochrome P-450 in the liver “first pass elimination“ of aβ-receptor blocking drug.Acta Pharmacol. Toxicol. 35:242–260 (1974).
M. Ervik. Gas Chromatographie determination of the secondary amine alprenolol, as its trifluoroacetyl derivative, at nanogram levels in biological fluids.Acta Pharm. Suec. 6:393–400 (1969).
D. Perrier, M. Gibaldi, and R. N. Boyes. Prediction of systemic availability from plasmalevel data after oral drug administration.J. Pharm. Pharmacol. 25:256–257 (1973).
B. Åblad, K. O. Borg, G. Johnsson, C. G. Regårdh, and L. Sölvell. Combined pharmacokinetic and pharmacodynamic studies on alprenolol and 4-hydroxy-alprenolol in man.Life Sci. 14:693–704 (1974).
M. Rowland, L. Z. Benet, and G. G. Graham. Clearance concepts in pharmacokinetics.J. Pharmacokin. Biopharm. 1:123–136 (1973).
S: Riegelman and M. Rowland. Effect of route of administration on drug disposition.J. Pharmacokin. Biopharm. 1:419–434 (1973).
R. Grundin, P. Moldéus, H. Vadi, S. Orrenius, C. von Bahr, D. Bäckström, and A. Ehrenberg. Drug metabolism in isolated rat liver cells. In D. Y. Cooper, O. Rosenthal, R. Snyder, and C. Wittmer (eds.),Advanced. Experimental Medical Biology, Vol. 58, Plenum Press, New York, 1975.
C. von Bahr, H. Vadi, P. Moldéus, and A. Norlin. Stoichiometric interaction of a beta-receptor blocking drug with fraction of liver cytochrome P-450 as a possible cause for its dose-dependent availability.Acta Pharmacol. Toxicol. 38:513–524 (1976).
T. Walle, J. Morrison, K. Walle, and E. Conradi. Simultaneous determination of propranolol and its active metabolite 4-hydroxypropranolol in plasma during chronic propranolol therapy. In Abstracts, Fourth Pharmacology-Toxicology Program, Symposium, N.I.H., November 1975, Washington D.C.
R. L. Dedrick, D. S. Zaharko, and R. J. Lutz. Transport and binding of methotrexatein vivo. J. Pharm. Sci. 60:882–890 (1973).
T. Tsuchiya and G. Levy. Relationship between dose and plateau levels of drugs eliminated by parallel first order and capacity limited kinetics.J. Pharm. Sci. 61:541–544 (1972).
R. Johansson, C. G. Regårdh, and J. Sjögren. Absorption of alprenolol in man from tablets with different rates of release.Acta Pharm. Suec. 8:59–70 (1971).
R. A. Branch, D. G. Shand, G. R. Wilkinson, and A. S. Nies. Increased clearance of antipyrine andd-propranolol after phenobarbital treatment in the monkey.J. Clin. Invest. 53:1101–1107 (1974).
D. Perrier and M. Gibaldi. Clearance and biological half-life as indices of intrinsic hepatic metabolism.J. Pharmacol. Exp. Ther. 191:17–24 (1974).
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This study was supported by the Swedish Medical Research Council (04X-3902, 04P-4933), the funds of the Karolinska Institutet, and the fund of Tore Nilsson. G. A. held a scholarship from the Association of the Swedish Pharmaceutical Industry (LIF).
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Alván, G., Lind, M., Mellström, B. et al. Importance of “first-pass elimination” for interindividual differences in steady-state concentrations of the adrenergicβ-receptor antagonist alprenolol. Journal of Pharmacokinetics and Biopharmaceutics 5, 193–205 (1977). https://doi.org/10.1007/BF01065395
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DOI: https://doi.org/10.1007/BF01065395