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Importance of patient selection when determining the significance of the CYP3A5 polymorphism in clinical trials

The Pharmacogenomics Journal volume 4, pages 362–364 (2004)Cite this article

We have followed with great interest the growing number of publications reporting the varying degrees of importance that cytochrome P450 3A5 (CYP3A5) plays in human drug metabolism. In vitro studies have identified a growing number of substrates for which CYP3A5 contributes significantly to their metabolism. Williams et al1 report that the contribution of CYP3A5 to midazolam hydroxylation can be readily measured due to the high turnover of midazolam by the enzyme. They also report significant CYP3A5 in vitro clearance values for alprazolam and triazolam, both benzodiazepines, diltiazem, a benzothiazepine, and tamoxifen, an antiestrogen commonly used in therapy for breast cancer. When these in vitro data are extrapolated to an in vivo outcome, the models confirm a significant pharmacokinetic difference between patients homozygous for the CYP3A5*3 allele (expressing very little to no CYP3A5) and patients homozygous for the CYP3A5*1 allele (expressing significant levels of CYP3A5).2

To date, there appears to be a growing contingent of researchers who are questioning the metabolic role of CYP3A5 relative to cytochrome P450 3A4 (CYP3A4) in vivo based on clinical studies. For example, Wong et al3 report that an observed interpatient variability in midazolam and vinorelbine clearances in chemotherapy patients cannot be related to the CYP3A5 genotype. Fukada et al4 claim to show evidence that large intragroup variations in nifedipine clearance in healthy male Japanese subjects have no relation to the CYP3A5 genotype, and thus conclude that the overall relevance of the CYP3A5 polymorphism in clinical trials needs to be re-evaluated. Furthermore, in a very thorough review of the literature, Thummel5 seems to imply that the previously assumed importance of the CYP3A5 polymorphism in the clinic may have been overstated.

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  1. Discovery Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, CT, USA

    R S Foti & M B Fisher

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  1. R S Foti
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Correspondence to M B Fisher.

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Foti, R., Fisher, M. Importance of patient selection when determining the significance of the CYP3A5 polymorphism in clinical trials. Pharmacogenomics J 4, 362–364 (2004). https://doi.org/10.1038/sj.tpj.6500286

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