Interaction of irinotecan (CPT-11) and its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) with human cytochrome P450 enzymes.
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.
Hanioka
Nobumitsu
N
Project Team for Pharmacogenetics, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan. hanioka@nihs.go.jp
Ozawa
Shogo
S
Jinno
Hideto
H
Tanaka-Kagawa
Toshiko
T
Nishimura
Tetsuji
T
Ando
Masanori
M
Sawada Ji
Jun-ichi
J
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002374:Catalase / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005978:Glutathione / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008861:Microsomes / Q000737:chemistry / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000077146:Irinotecan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D002374:Catalase; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005978:Glutathione; D003676:Deferoxamine; D002166:Camptothecin