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Xenobiotica
the fate of foreign compounds in biological systems
Volume 37, 2007 - Issue 9
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Research Article

Approach to predict the contribution of cytochrome P450 enzymes to drug metabolism in the early drug-discovery stage: The effect of the expression of cytochrome b5 with recombinant P450 enzymes

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Pages 986-999 | Received 16 Apr 2007, Accepted 09 Aug 2007, Published online: 13 Aug 2009
 

Abstract

In order to evaluate the potential adverse effects due to genetic polymorphism and/or inter-individual variation, it is necessary to calculate the cytochrome P450 (CYP) contribution to the metabolism of new drugs. In the current study, the in vitro intrinsic clearance (CLint) values of marker substrates and drugs were determined by measuring metabolite formation and substrate depletion, respectively. Recombinant CYP microsomes expressing CYP2C9, CYP2C19 and CYP3A4 with co-expressed cytochrome b5 were used, but those expressing CYP1A2 and CYP2D6 did not have co-expressed cytochrome b5. The following prediction methods were compared to determine the CLint value using data from recombinant CYP enzymes: (1) relative CYP enzyme content in human liver microsomes; (2) relative activity factor (RAF) estimated from the Vmax value; and (3) RAF estimated from the CLint value. Estimating RAF from CLint proved the most accurate prediction method among the three tested, and differences in the CYP3A4 marker reactions did not affect its accuracy. The substrate depletion method will be useful in the early drug-discovery stage when the main metabolite and/or metabolic pathway has not been identified. In addition, recombinant CYP microsomes co-expressed with cytochrome b5 might be suitable for the prediction of the CLint value.

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