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 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.
Footnotes
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This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences (MPJ-6) of the Organization for Pharmaceutical Safety and Research of Japan.
- Abbreviations used are::
- CPT-11
- 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin
- P450
- cytochrome P450
- SN-38
- 7-ethyl-10-hydroxycamptothecin
- APC
- 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin
- NPC
- 7-ethyl-10-[4-(1-piperidino)-1-amino]carbonyloxycamptothecin
- HPLC
- high-performance liquid chromatography
- b5
- cytochrome b5
- L-754,394
- N-(2(R)-hydroxy-1(S)-indanyl)-5-(2(S)-(1,1-dimethylethylaminocarbonyl)-4-(furo(2,3-b)pyridin-5-yl)methyl)piperazin-1-yl)-4(S)-hydroxy-2(R)-phenylmethylpentanamide
- Received October 19, 2001.
- Accepted December 18, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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