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

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Citation

Hanioka N, Ozawa S, Jinno H, Tanaka-Kagawa T, Nishimura T, Ando M, Sawada Ji J

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

Drug Metab Dispos. 2002 Apr;30(4):391-6.

PubMed ID
11901092 [ View in PubMed
]
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 affected by either compound. Furthermore, CPT-11 and SN-38 were suggested to be mechanism-based inactivators of CYP3A4. The k(inact) and K(I) values of CPT-11 and SN-38 were 0.06 min(-1) and 24 microM and 0.10 min(-1) and 26 microM, 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
SN-38Cytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Details