%0 Journal Article %A Nobumitsu Hanioka %A Shogo Ozawa %A Hideto Jinno %A Toshiko Tanaka-Kagawa %A Tetsuji Nishimura %A Masanori Ando %A Jun-ichi Sawada %T Interaction of Irinotecan (CPT-11) and Its Active Metabolite 7-Ethyl-10-Hydroxycamptothecin (SN-38) with Human Cytochrome P450 Enzymes %D 2002 %R 10.1124/dmd.30.4.391 %J Drug Metabolism and Disposition %P 391-396 %V 30 %N 4 %X 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 6β-hydroxylation) activity with Ki values of 129 and 121 μM, 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 Ki values being 181 and 156 μM, respectively. On the other hand, CYP1A2 (phenacetinO-deethylation), CYP2B6 (7-ethoxycoumarinO-deethylation), CYP2C8 (paclitaxel 6α-hydroxylation), CYP2C19 (S-mephenytoin 4′-hydroxylation), CYP2D6 (bufuralol 1′-hydroxylation), and CYP2E1 (chlorzoxazone 6-hydroxylation) were hardly affected by either compound. Furthermore, CPT-11 and SN-38 were suggested to be mechanism-based inactivators of CYP3A4. The kinact andKI values of CPT-11 and SN-38 were 0.06 min−1 and 24 μM and 0.10 min−1 and 26 μM, respectively. However, no inactivation of CYP2A6 and CYP2C9 by SN-38 was observed. These results mean that CPT-11 and SN-38 interact with human P450 isoforms, such as CYP2A6, CYP2C9, and CYP3A4, in vitro and imply that the significant drug interactions involving CPT-11 may be caused by a mechanism-based inactivation of CYP3A4 by SN-38 as an active metabolite of CPT-11 rather than competitive inhibition. The American Society for Pharmacology and Experimental Therapeutics %U https://dmd.aspetjournals.org/content/dmd/30/4/391.full.pdf