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Institut Bergonié and Université Victor Segalen Bordeaux 2, 33076 Bordeaux-cedex, France [M. C. H., J. R.]; Sydney Cancer Centre, Royal Prince Alfred Hospital, 2050 Sydney, Australia [L. R.]; Laboratoire de Pharmacologie, Faculté de Médecine, 29200 Brest-cedex, France [C. R.]; and Rhône-Poulenc Rorer, 92165 Antony-cedex, France [L. V.]
Irinotecan (CPT-11) is a water-soluble analogue of camptothecin showing activity in colon cancer. Recently, we identified a major metabolite of CPT-11 in patients' plasma, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC), which is produced by the oxidation of the distal piperidine ring (P. Rivory et al., Cancer Res., 56: 3689–3694, 1996). As with all active camptothecin derivatives, CPT-11 is subject to spontaneous interconversion between a lactone and a carboxylate form in aqueous media. The kinetics of biotransformation of the two forms of CPT-11 into APC was studied using pooled human liver microsomes. The formation of APC was characterized by the following parameters: Km = 18.4 ± 1.4 and 39.7 ± 11.6 µM; and Vmax = 26.0 ± 0.6 and 13.4 ± 1.7 pmol/min/mg protein for the lactone and carboxylate forms of CPT-11, respectively. This reaction was found to be catalyzed principally by cytochrome P-450 (CYP) 3A because of three key results: (a) the CYP 3A-selective inhibitors ketoconazole (1 µM) and troleandomycin (100 µM) inhibited APC formation by 98 and 100%, respectively, mostly in a competitive way; (b) using microsomes from transfected lymphoblastoid cells expressing specific CYPs, we found that only those from CYP 3A4 cDNA-transfected cells transformed CPT-11 into APC; and (c) using 15 individual preparations of human liver microsomes, we observed highly significant correlations between the activity of CPT-11 metabolism into APC and both immunoreactivity with anti-CYP 3A antibodies and testosterone 6ß hydroxylation, an activity specifically mediated by CYP 3A. The effect on this metabolism of 11 drugs used at 100 µM was studied with CPT-11 lactone at 25 µM. Amikacin, Bactrim, ciprofloxacin, rocephine, 5-fluorouracil, metoclopramide, morphine, and paracetamol had no effect, but ondansetron, loperamide, and racecadotril inhibited this pathway by 25, 50, and 50%, respectively. These concentrations exceed those expected in vivo. APC formation in patients may thus be influenced by coadministered ketoconazole therapy and may decline after administration of CPT-11 because of the lactonolysis of the latter.
1 Supported by grants from the Ligue Nationale Française contre le Cancer (Comités Départementaux de la Charente-Maritime et de la Dordogne).
2 To whom requests for reprints should be addressed, at Institut Bergonié and Université Victor Segalen Bordeaux 2, 180 rue de Saint-Genès, 33076 Bordeaux-cedex, France.
Received 8/19/97. Accepted 12/ 3/97.
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