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P450 humanized mice for the study of xenobiotics CYP3A4 as a paradigm

, : P450 humanized mice for the study of xenobiotics CYP3A4 as a paradigm. FASEB Journal 18(4-5): Abst 793 2

Animal models are widely used to examine metabolism, pharmacology and toxicology of xenobiotics including therapeutic agents. However, there are marked notable species differences in the expression and enzymatic functions of P450s between mice and rats, and humans. This is especially notable between mice and rats, commonly used experimental models, and humans. Human P450-expressing transgenic mice were generated using genomic clones, and mouse lines expressing the CYP2D6 and CYP3A4 genes were characterized and found to accurately express the corresponding enzymes higher than those found in human tissues. Highly sensitive LC-MS/MS was developed to perform drug metabolism and pharmacokinetic analyses using probe drugs. These novel P450 humanized mouse lines overcome the gap of species differences and offer a better system to study drug metabolism and disposition, and drug-drug interactions for the prediction of drug/chemical effects in humans. Moreover, these mice can serve as whole intact animal models for exploring endogenous substrates for human P450s, examining their biotransformations, and elucidating physiological consequences of human P450 expression in an integrated whole animal system. A CYP3A4 humanized mouse was produced that expressed high levels of enzymatically active protein in the gut. These mice exhibited altered pharmacokinetics to orally administered CYP3A4 substrates. They might be useful for the preclinical evaluation of orally administered drugs that are CYP3A4 substrates and to determine the effects of inhibitors of CYP3A4 on pharmacokinetics.


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Böcher, W.O.; Schuchmann, M.; Link, R.; Hillenbrand, H.; Rahman, F.; Sprinzl, M.; Mudter, J.; Löhr, H.F.; Galle, P.R., 2006: Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-alpha therapy. Background: The efficacy of consensus interferon (CIFN), a synthetic IFN with optimised in vitro activity, was assessed in chronic hepatitis C virus (HCV) patients who had failed the pretreatment with interferon-alpha (IFN alpha) and ribavirin. Me...

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