PMID: 11901092Mar 20, 2002Paper

Interaction of irinotecan (CPT-11) and its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) with human cytochrome P450 enzymes

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Nobumitsu HaniokaJun-ichi Sawada Ji

Abstract

The inhibition and mechanism-based inactivation potencies of irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin; CPT-11) and its active metabolite (7-ethyl-10-hydroxycamptothecin; SN-38) for human cytochrome P450 (P450) enzymes were investigated to evaluate the potential for drug interactions involving CPT-11 using microsomes from insect cells expressing specific human P450 isoforms. The mechanism and potential for interaction were examined by Lineweaver-Burk analysis, and NADPH-, time- and concentration-dependent effects were observed. CPT-11 and SN-38 competitively inhibited CYP3A4 (testosterone 6 beta-hydroxylation) activity with K(i) values of 129 and 121 microM, respectively. CYP2A6 (coumarin 7-hydroxylation) and CYP2C9 (diclofenac 4'-hydroxylation) activities exhibited a mixed type of inhibition comprising competitive and noncompetitive components in response to SN-38, the K(i) values being 181 and 156 microM, respectively. On the other hand, CYP1A2 (phenacetin O-deethylation), CYP2B6 (7-ethoxycoumarin O-deethylation), CYP2C8 (paclitaxel 6 alpha-hydroxylation), CYP2C19 (S-mephenytoin 4'-hydroxylation), CYP2D6 (bufuralol 1'-hydroxylation), and CYP2E1 (chlorzoxazone 6-hydroxylation) were hardly af...Continue Reading

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