The use of in vitro metabolism studies in the understanding of new drugs

https://doi.org/10.1016/1056-8719(93)90054-IGet rights and content

Abstract

In vitro models derived from various animal species are routinely used for the evaluation of pharmacological potency and toxicological potential of new drug candidates. It is well known that metabolism of the drug molecule often contributes to the efficacy and toxicity observed in vivo. In vitro metabolism studies conducted in biological matrixes ranging from intact organ, tissue slice to subcellular fraction offer the advantage of reduced complexity of the study system, and allow the evaluation of intrinsic metabolic potential or mechanism with respect to a specific reaction. In addition, in vitro systems derived from various animal species offer the possibility of comparing metabolic pathways among species, including humans, before a compound can be tested clinically. Two areas of particular interest for the use of in vitro studies in the understanding new drugs are 1) the relationship of metabolic pathway and pharmacodynamics and 2) the prediction of drug interaction potential in humans. To illustrate these aspects, I review metabolism studies on losartan, an angiotensin-II receptor antagonist currently in phase-III clinical development for hypertension, and cyclosporin A, a widely prescribed immunosuppressant.

References (52)

  • J. Caldwell

    Clinically relevant drug interaction—An overview

  • D.J. Carini et al.

    Nonpeptide angiotensin II receptor antagonist: The discovery of a series of N-(biphenylmethyl) imidazoles as potent, orally active antihypertensives

    J Med Chem

    (1991)
  • T. Chang et al.

    Selective inhibition of rat hepatic microsomal cytochrome P450 I. Effect of the in vivo administration of cimetidine

    J Pharm Exp Ther

    (1992)
  • T. Chang et al.

    Selective inhibition of rat hepatic microsomal cytochrome P-450 II. Effect of the in vitro administration of cimetidine

    J Pharm Exp Ther

    (1992)
  • S.H.L. Chiu et al.

    Comparative in vivo and in vitro metabolism of ivermectin in steers, sheep, swine and rat

    Drug Metab Rev

    (1987)
  • D. Christ et al.

    Formation and disposition of EXP3174, a pharmacologically active metabolite of the novel angiotensin II receptor antagonist Losartan

  • U. Christian et al.

    Investigations on the metabolic pathways of cyclosporine: II. Elucidation of the metabolic pathways in vitro by human liver microsomes

    Xenobiotica

    (1991)
  • J. Combalbert et al.

    Metabolism of cyclosporin A. IV. Purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporin A oxidase) as a product of P450 IIIA gene subfamily

    Drug Metab Dispos

    (1989)
  • M.J. Crawford et al.

    The use of animal subcellular fractions to study type II metabolism of xenobiotics

  • D.E. Duggan et al.

    Physiological disposition of HMG-CoA-reductase inhibitor

    Drug Metab Rev

    (1990)
  • R.W. Estabrook et al.

    The use of animal subcellular fractions to study type I metabolism of xenobiotics

  • G. Fabre et al.

    Metabolism of cyclosporin A. I. Study in freshly isolated rabbit hepatocytes

    Drug Metab Dispos

    (1987)
  • I. Fabre et al.

    Metabolism of cyclosporin A. III. Interaction of the macrolide antibiotic, erythromycin, using rabbit hepatocytes and microsomal fractions

    Drug Metab Dispos

    (1988)
  • D.J. Freeman et al.

    Evaluation of cyclosporin metabolites

    Br J Clin Pharmacol

    (1991)
  • C. Ged et al.

    The increase in urinary excretion of 6β-hydroxy-cortisol as a marker of human hepatic cytochrome P450 IIIA3 induction

    Br J Clin Pharmacol

    (1989)
  • J.R. Gillette

    Techniques for studying drug metabolism in vitro

  • Cited by (28)

    • Updates on Cytochrome P450-Mediated Cardiovascular Drug Interactions

      2010, Disease-a-Month
      Citation Excerpt :

      Rifampin has been demonstrated to increase verapamil clearance by 32-fold.35 Calcium channel blockers inhibit the metabolism of cyclosporine.36 Diltiazem in doses as low as 10 mg increased the bioavailability of cyclosporine and resulted in the need for a lower dose to maintain efficacy or avoid toxic effects.37

    • Interspecies difference in liver-specific functions and biotransformation of testosterone of primary rat, porcine and human hepatocyte in an organotypical sandwich culture

      2009, Toxicology Letters
      Citation Excerpt :

      The use of such a functioning human (or porcine) metabolic system will help to increase and refine the relevance of pharmacokinetic and toxicological screenings for man. An appropriate in vitro model offers the advantage of reduced complexity of the study system and allows the evaluation of intrinsic metabolic potentials or mechanisms with respect to a specific reaction (Chiu, 1993). The in vitro model has to fulfil several criteria: it has to be stable and reproducible, and hepatocytes have to be cultivated in an organotypic way, which means that the cells have to keep their ability to perform both primary metabolism and biotransformation (Cross and Bayliss, 2000).

    • Fetal hepatic drug elimination

      1999, Pharmacology and Therapeutics
    View all citing articles on Scopus
    View full text