Relative roles of CYP2C19 and CYP3A4/5 in midazolam 1'-hydroxylation.
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.
Emoto
C
C
Department of Pharmacokinetics Dynamics Metabolism, Pfizer Global Research and Development, Taketoyo, Aichi, Japan.
Iwasaki
K
K
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000502:physiology*; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam