Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data

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Abstract

As a new approach to predicting in vivo drug metabolism in humans, scaling of in vivo metabolic clearance from in vitro data obtained using human liver microsomes or hepatocytes is described in this review, based on the large number of literature data. Successful predictions were obtained for verapamil, loxtidine (lavoltidine), diazepam, lidocaine, phenacetin and some other compounds where CLint,in vitro is comparable with CLint,in vivo. On the other hand, for some metabolic reactions, differences in CLint,in vitro and CLint, in vivo greater than 5-fold were observed. The following factors are considered to be the cause of the differences: (1) metabolism in tissues other than liver, (2) incorrect assumption of rapid equilibrium of drugs between blood and hepatocytes, (3) presence of active transport through the sinusoidal membrane, and (4) interindividual variability. Furthermore, the possibility of predicting in vivo drug metabolic clearance from results obtained using a recombinant system of human P450 isozyme was described for a model compound, YM796, where the predicted metabolic clearances obtained from the recombinant system, taking account of the content of the P450 isozyme CYP3A4 in the human microsomes, were comparable with the observed clearances using human liver microsomes containing different amounts of CYP3A4. Even in the case where the first-pass metabolism exhibits nonlinearity, it appears to be possible to predict in vivo metabolic clearance from in vitro metabolic data.

References (84)

  • T. Seddon et al.

    Comparative drug metabolism of diazepam in hepatocytes isolated from man, rat, monkey and dog

    Biochem. Pharmacol.

    (1989)
  • H. Suzuki et al.

    Applications and prospects for physiologically based pharmacokinetic (PB- PK) models involving pharmaceutical agents

    Toxicol. Lett.

    (1995)
  • A.B. Ahmad et al.

    Models of hepatic drug clearance: discrimination between the “well-stirred” and “parallel-tube” models

    J. Pharm. Pharmacol.

    (1983)
  • M.J. Bargetzi et al.

    Lidocaine metabolism in human liver microsomes by cytochrome P450IIIA4

    Clin. Pharmacol. Ther.

    (1989)
  • M.K. Bayliss et al.

    Prediction of intrinsic clearance of loxtidine from kinetic studies in rat, dog and human hepatocytes

    Biochem. Soc. Trans.

    (1990)
  • A.H. Beckett et al.

    The distribution, metabolism and excretion of mexiletine in man

    Postgrad. Med. J.

    (1977)
  • H. Boxenbaum

    Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance extrapolation of data to benzodiazepines and phenytoin

    J. Pharmacokinet. Biopharm.

    (1980)
  • H. Boxenbaum

    Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics

    J. Pharmacokinet. Biopharm.

    (1982)
  • F. Broly et al.

    Mexiletine metabolism in vitro by human liver

    Drug Metab. Dispos.

    (1990)
  • E. Chan et al.

    Stereochemical aspects of warfarin in patients receiving chronic therapy

    Br. J. Clin. Pharmacol.

    (1984)
  • K. Chiba et al.

    The role of mephenytoin 4′-hydroxylase in imipramine metabolism by human liver microsomes: a two enzyme kinetic analysis of N-demethylation and 2-hydroxylation

    Br. J. Clin. Pharmacol.

    (1994)
  • M. Chiba et al.

    Role of cytochrome P4503A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor

    Drug Metab. Dispos.

    (1996)
  • D.A. Ciraulo et al.

    Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers

    Clin. Pharmacol. Ther.

    (1988)
  • R.L. Dedrick

    Animal scale-up

    J. Pharmacokinet. Biopharm.

    (1973)
  • F.S. Eberts et al.

    Disposition of 14C-alprazolam, a new anxiolytic-antide-pressant, in man

    Pharmacologist

    (1980)
  • B.G. Hardy et al.

    Lack of effect of cimetidine on the metabolism of quinidine: effect on renal clearance

    Int. J. Clin. Pharmacol. Ther. Toxicol.

    (1988)
  • M.F. Hebert et al.

    Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction

    Clin. Pharmacol. Ther.

    (1992)
  • B.-A. Hoener

    Predicting the hepatic clearance of xenobiotics in humans from in vitro data

    Biopharm. Drug Dispos.

    (1994)
  • Y. Horai et al.

    Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese

    Clin. Pharmacol. Ther.

    (1989)
  • J.B. Houston

    Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance

    Biochem. Pharmacol.

    (1994)
  • S. Imaoka et al.

    Lidocaine metabolism by human cytochrome P-450s purified from hepatic microsomes: comparison of those with rat hepatic cytochrome P-450s

    J. Pharmacol. Exp. Ther.

    (1990)
  • T. Iwatsubo et al.

    Prediction of in vivo drug disposition from in vitro data based on physiological pharmacokinetics

    Biopharm. Drug Dispos.

    (1996)
  • K.A. Johansson et al.

    Binding of two adrenergic beta-receptor antagonists, alprenolol and H 93/26, to human serum proteins

    Acta Pharm. Suec.

    (1974)
  • R. Kato et al.

    The importance of substrate concentration in determining cytochromes P450 therapeutically relevant in vivo

    Pharmacogenetics

    (1994)
  • J.B. Keenaghan et al.

    The tissue distribution, metabolism and excretion of lidocaine in rats, guinea pigs, dogs and man

    J. Pharmacol. Exp. Ther.

    (1972)
  • M. Kim et al.

    Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes

    Drug Metab. Dispos.

    (1992)
  • U. Klotz et al.

    Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat

    J. Pharmacol. Exp. Ther.

    (1976)
  • H.K. Kroemer et al.

    Predictability of the in vivo metabolism of verapamil from in vitro data: contribution of individual metabolic pathways and stereoselective aspects

    J. Pharmacol. Exp. Ther.

    (1992)
  • J.H. Lin

    Species similarities and differences in pharmacokinetics

    Drug Metab. Dispos.

    (1995)
  • J.H. Lin et al.

    Correlation between in vitro and in vivo drug metabolism rate: oxidation of ethoxybenzamide in rat

    J. Pharmacokinet. Biopharm.

    (1978)
  • G. Mikus et al.

    Pharmacokinetics and metabolism of quinidine in extensive and poor metabolizers of sparteine

    Eur. J. Clin. Pharmacol.

    (1986)
  • A.K. Miller et al.

    Excretion of tolbutamide metabolites in young and old subjects

    Eur. J. Clin. Pharmacol.

    (1990)
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