Role of Human Liver Cytochrome P450 2C9 in the Metabolism of a Novel α4β1/α4β7 Dual Antagonist, TR-14035

TSUDA-TSUKIMOTO Minoru, OGASAWARA Yuko, KUME Toshiyuki

doi:10.2133/dmpk.20.127

The metabolism of a novel dual antagonist for α4β1/α4β7 integrin, TR-14035, and the role of polymorphic enzyme responsible for this metabolism were investigated. Human liver microsomes catalyzed the NADPH-dependent metabolism of TR-14035 to a primary metabolite, O-desmethyl TR-14035. This formation was completely blocked by both sulfaphenazole, a selective CYP2C9 inhibitor, and CYP2C9 antibody, whereas potent inhibitors selective for other CYPs exhibited little effects. Of 12 recombinant CYPs examined, O-desmethyl metabolite was principally formed by CYP2C9. CYP1A1, an extrahepatic enzyme, also had this activity (about one-fourth of CYP2C9). Utilizing recombinant CYP2C9^*1, K_m and V_max/K_m values of 23.3 μM and 0.284 μL/min/pmol CYP2C9, respectively, were obtained for the O-desmethyl formation, which were quite similar to those in CYP2C9^*2 enzyme. In contrast, V_max/K_m value in recombinant CYP2C9^*3 was approximately one-sixth of CYP2C9^*1 and ^*2. In agreement, kinetics studies using human liver microsomes with CYP2C9^*1/^*1, ^*2/^*2 and ^*3/^*3 genotypes revealed that the V_max/K_m value in ^*2/^*2 microsomes was comparable to that in wild type microsomes, in contrast, that in ^*3/^*3 microsomes was reduced. These results demonstrate CYP2C9 is a primary enzyme mediating the O-desmethylation of TR-14035 in human liver. In homozygotes of CYP2C9^*3, the metabolic clearance of TR-14035 should be decreased compared with homozygotes of CYP2C9^*1 or 2.<br>

Role of Human Liver Cytochrome P450 2C9 in the Metabolism of a Novel α4β1/α4β7 Dual Antagonist, TR-14035

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Role of Human Liver Cytochrome P450 2C9 in the Metabolism of a Novel α4β1/α4β7 Dual Antagonist, TR-14035

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この論文をさがす

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収録刊行物

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キーワード

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