In vitro methods in human drug biotransformation research: implications for cancer chemotherapy.
Anticancer drugs have a complex pharmacological and toxicological profile with a narrow therapeutic index. It is therefore critical to understand the factors that contribute to the marked intersubject variability in the pharmacokinetics and pharmacodynamics often observed with anticancer compounds. Since hepatic and extra-hepatic drug metabolism represents a major drug disposition pathway, extensive efforts are made to thoroughly investigate metabolism of anticancer compounds during the pre-clinical and clinical development phases as well as to address issues encountered during the clinical use of an approved drug. In recent years there has been a significant paradigm shift in pre-clinical/non-clinical drug metabolism studies. Most importantly, this has included a reduced reliance on animal models and increased use of human tissues (i.e. human liver microsomes and other cellular fractions, primary culture of human hepatocytes, cDNA expressed human-specific enzymes and cell-based reporter assays). Typically, experiments are performed using these tools to identify the phase I and/or phase II enzymes involved in metabolism of the drug/investigational agent and for metabolic fingerprinting. Additionally, issues pertaining to the rate, extent and mechanism(s) of the inhibition or induction of the metabolic pathways are also investigated. These studies provide important clues about various aspects of the disposition of a therapeutic agent including first-pass metabolism, elimination half-life, overall bioavailability and the potential for drug-drug interactions. The methodologies used for in vitro assessment of drug metabolism and their applications to drug development and clinical therapeutics with special emphasis on anticancer drugs are reviewed in this manuscript.
Hariparsad
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College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
Sane
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RS
Strom
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Desai
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PB
D000970:Antineoplastic Agents / Q000378:metabolism*; D001711:Biotransformation; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
D000970:Antineoplastic Agents