CYP3A4 and CYP3A5 catalyse the conversion of the N-methyl-D-aspartate (NMDA) antagonist CJ-036878 to two novel dimers.
CJ-036878, N-(3-phenethoxybenzyl)-4-hydroxybenzamide, was developed as an antagonist of the N-methyl-D-aspartate receptor NR2B subunit. Two dimeric metabolites, CJ-047710 and CJ-047713, were identified from the incubation mixture with CJ-036878 in human liver microsomes (HLM). The identification of the enzymes involved in the formation of these dimeric metabolites was investigated in the current study. Inhibition of the formation of CJ-047710 and CJ-047713 in pooled HLM by 1-aminobenztriazole, SKF-525A, and ketoconazole were observed. Ketoconazole played a significant role in inhibiting formation of these two metabolites in a concentration-dependent manner. Recombinant CYP3A4 and CYP3A5 exhibited a markedly high activity toward the formation of CJ-047710 and CJ-047713 from CJ-036878, but the contribution of other CYP enzymes to these formations was at a very low level or negligible. The formation of CJ-047710 and CJ-047713 in pooled HLM, CYP3A4, and CYP3A5 showed sigmoid characteristics. S50 values for CJ-047710 and CJ-047713 formation in HLM were almost equivalent with those for CYP3A4 and CYP3A5. For the CYP3A enzymes, maximal clearance due to auto-activation values for CJ-047710 and CJ-047713 formation catalysed by CYP3A5 were 3.6- and 3.1-fold higher than those catalysed by CYP3A4. This is the first report that shows both CYP3A4 and CYP3A5 simultaneously contribute to dimerization through oxidative C-C and C-O coupling reactions.
Emoto
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Department of Pharmacokinetics Dynamics Metabolism, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Japan, Inc., Taketoyo, Aichi, Japan.
Nishida
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Hirai
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Iwasaki
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D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D019281:Dimerization; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D010084:Oxidation-Reduction; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D001549:Benzamides; C529487:N-(3-phenethoxybenzyl)-4-hydroxybenzamide; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C103544:4-hydroxybenzamide; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human