In Vitro Inhibitory Effect of 1-A minobenzotriazole on Drug Oxidations Catalyzed by Human Cytochrome P450 Enzymes: A Comparison with SKF-525A and Ketoconazole

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  • EMOTO Chie
    Department of Pharmacokinetics Dynamics Metabolism, Nagoya Laboratories, Pfizer Inc.
  • MURASE Shigeo
    Department of Pharmacokinetics Dynamics Metabolism, Nagoya Laboratories, Pfizer Inc.
  • SAWADA Yasufusa
    Department of Pharmacokinetics Dynamics Metabolism, Nagoya Laboratories, Pfizer Inc.
  • JONES Barry C.
    Department of Pharmacokinetics Dynamics Metabolism, Sandwitch Laboratories, Pfizer Inc.
  • IWASAKI Kazuhide
    Department of Pharmacokinetics Dynamics Metabolism, Nagoya Laboratories, Pfizer Inc.

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1-Aminobenzotriazole (ABT) is widely used as a non-specific inhibitor of animal cytochrome P450 (CYP). In the present study, the inhibitory effect of ABT was investigated on drug oxidations catalyzed by human CYP isoforms. This inhibitory effect was compared with that of SKF-525A, another non-specific inhibitor, and ketoconazole, a potent inhibitor of CYP3A. Bacurovirus-expressed recombinant human CYP isoforms were used as an enzyme source. The specific activities for human CYP isoforms are: phenacetin O-deethylation, for CYP1A2; diclofenac 4'-hydroxylation, for CYP2C9; S-mephenytoin 4'-hydroxylation, for CYP2C19; bufuralol 1'-hydroxylation, for CYP2D6; chlorzoxazone 6-hydroxylation, for CYP2E1; testosterone 6β-hydroxylation, nifedipine oxidation, and midazolam 1'-hydroxylation, for CYP3A4. ABT inhibited both CYP1A2-dependent activity (Ki=330 μM) and CYP2E1-dependent activity (Ki=8.7 μM). In contrast, SKF-525A weakly inhibited CYP1A2-dependent activities (46% inhibition at 1200 μM) and CYP2E1-dependent activities (65% inhibition at 1000 μM). ABT exhibited the highest Ki value for CYP2C9-dependent diclofenac 4'-hydroxylation among those determined by this assay (Ki=3500 μM). Moreover, SKF-525A showed strong inhibition of CYP2D6-dependent bufuralol 1'-hydroxylation (Ki=0.043 μM). Ketoconazole inhibited all tested drug oxidations, however, its inhibitory effect on CYP1A2-dependent activities was very weak (50% inhibition at 120 μM). ABT, SKF-525A, and ketoconazole showed different selectivity and had a wide range of Ki values for the drug oxidations catalyzed by human CYP enzymes. Therefore, we conclude that inhibitory studies designed to predict the contribution of CYP enzymes to the metabolism of certain compounds should be performed using multiple CYP inhibitors, such as ABT, SKF-525A, and ketoconazole.

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