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Liver-Based In Vitro Technologies for Drug Biotransformation Studies - A Review

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Early understanding of the metabolic pathway and potential interaction of new drug candidates with other drugs is one of the goals of preclinical studies in the drug discovery process. Although other body organs are involved in drug biotransformation, the liver is the predominant organ of metabolism for a wide range of endogenous compounds and xenobiotics. The set of enzymes contained in the cytochrome P450 superfamily present predominantly in the liver have been identified as the single most important agent of drug metabolism and have formed the bedrock of most matured technologies for in vitro drug biotransformation studies. With the development of a number of liver-based technologies, in vitro metabolism has gained significant popularity in the past three decades. This has come in response to several demanding factors including the questionable relevance of data from animal studies; the high cost and stringent regulatory and ethical requirement, as well as safety issues involved with studies using human subjects; and the need for high throughput due to the wide range of chemical entities for routine investigations. These technologies which vary from whole liver to subcellular fractions have found ready application in generating the desired information on the substrate and inhibitor specificity of most metabolic enzymes. This paper reviews such technologies as isolated fresh liver; liver slices; primary, cultured and cryopreserved hepatocytes; microsomes; cytosolic fractions; and purified or heterologously expressed drug-metabolizing enzymes. It highlights the general principles of in vitro enzyme kinetics and the factors that determine the choice of each in vitro technology for biotransformation studies.

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Keywords: S9 fractions; UDT-glucuronosyltransferase; biotransformation; cofactors; cytochrome P450; in vitro metabolism; liver cytosol; liver slices; microsomes; subcellular fractions

Document Type: Research Article

Publication date: February 1, 2012

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  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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