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Xenobiotica. 2007 Jun;37(6):592-603.

Relative roles of CYP2C19 and CYP3A4/5 in midazolam 1'-hydroxylation.

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Department of Pharmacokinetics Dynamics Metabolism, Pfizer Global Research and Development, Taketoyo, Aichi, Japan.


1. During the characterization of recombinant CYP2C19, it was observed that this enzyme metabolized midazolam, which is generally regarded as CYP3A4/5 substrate, and we therefore decided to pursue this observation further. 2. CYP2C19 showed a Michaelis-Menten pattern for midazolam 1'-hydroxylation and was inhibited by (+)-N-3-benzylnirvanol and S-mephenytoin, which are a standard potent inhibitor and a substrate of CYP2C19, respectively. 3. The inhibitory potency by CYP3A4/5 inhibitor on the midazolam 1'-hydroxylation in human liver microsomes (HLM) was correlated with the CYP3A4/5 specific catalytic activity, but such correlation was not observed in CYP2C19 enzyme. The in vitro intrinsic clearance value for midazolam 1'-hydroxylation was not changed by the addition of (+)-N-3-benzylnirvanol in four individual HLM preparations. 4. These results indicated that although CYP2C19 is capable of catalyzing midazolam 1'-hydroxylation, CYP3A4/5 play a more important role.

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