In vitro inhibitory effect of 1-aminobenzotriazole on drug oxidations in human liver microsomes: a comparison with SKF-525A.
1-Aminobenzotriazole (ABT) is extensively used as a non-specific cytochrome P450 (CYP) inhibitor. In this study, the inhibitory effect of ABT on CYP-dependent drug oxidations was investigated in human liver microsomes (HLM) and compared with that of SKF-525A, another non-specific inhibitor. The following probe activities for human CYP isoforms were determined using pooled HLM: phenacetin O-deethylation (CYP1A2); diclofenac 4'-hydroxylation (CYP2C9); S-mephenytoin 4'-hydroxylation, (CYP2C19); bufuralol 1'-hydroxylation (CYP2D6); chlorzoxazone 6-hydroxylation (CYP2E1); midazolam 1'-hydroxylation, nifedipine oxidation, and testosterone 6beta-hydroxylation (CYP3A). ABT had the strongest inhibitory effect on the CYP3A-dependent drug oxidations and the weakest effect on the diclofenac 4'-hydroxylation. SKF-525A potently inhibited the bufuralol 1'-hydroxylation, but weakly inhibited chlorzoxazone 6-hydroxylation. The inhibitory effects of ABT and SKF-525A were increased by preincubation in some probe reactions, and this preincubation effect was greater in ABT than in SKF-525A. The remarkable IC50 shift (> 10 times) by preincubation with ABT was observed on the phenacetin O-deethylation, chlorzoxazone 6-hydroxylation, and midazolam 1'-hydroxylation. In conclusion, ABT and SKF-525A had a wide range of IC50 values in inhibiting the drug oxidations by HLM with and without preincubation.
Emoto
Chie
C
Department of Pharmacokinetics Dynamics Metabolism, Nagoya Laboratories, Pfizer Japan Inc., Taketoyo, Aichi, Japan.
Murase
Shigeo
S
Sawada
Yasufusa
Y
Iwasaki
Kazuhide
K
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011335:Proadifen / Q000494:pharmacology*; D013379:Substrate Specificity; D014230:Triazoles / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D014230:Triazoles; C033020:1-aminobenzotriazole; D011335:Proadifen