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Research ArticleArticle

Biosynthesis of an Aminopiperidino Metabolite of Irinotecan [7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] by Human Hepatic Microsomes

Marie-Christine Haaz, Christian Riché, Laurent P. Rivory and Jacques Robert
Drug Metabolism and Disposition August 1998, 26 (8) 769-774;
Marie-Christine Haaz
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Christian Riché
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Laurent P. Rivory
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Jacques Robert
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Abstract

Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] is a water-soluble analogue of camptothecine used in the second-line treatment of advanced colon cancer. Recently, we identified, in the plasma of patients and in human liver microsomal incubations, the presence of a new metabolite of irinotecan, 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine (NPC), which is produced by cleavage of the distal piperidine ring of irinotecan. The kinetics of biotransformation of the lactone and carboxylate forms of irinotecan into NPC were studied using human liver microsomes. The formation of NPC was characterized by the following parameters:KM = 48.2 ± 6.8 and 273 ± 122 μM and Vmax = 74.1 ± 4.9 and 78.6 ± 27.7 pmol/min/mg of protein for the lactone and carboxylate forms of irinotecan, respectively. Interestingly, there was no formation of NPC from 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecine, a major metabolite of irinotecan that has an open distal piperidine ring and could be considered a possible metabolic precursor of NPC. The transformation of irinotecan into NPC was found to be catalyzed principally by cytochrome P450 (CYP) 3A, based on three key results, as follows: 1) the CYP3A-selective inhibitors ketoconazole (1 μM) and troleandomycin (100 μM) inhibited NPC formation by 99 and 100%, respectively; 2) of a series of microsomal preparations from transfected lymphoblastoid cells expressing specific CYPs, only those from CYP3A4 cDNA-transfected cells transformed irinotecan into NPC; and 3) incubations with 15 individual preparations of human liver microsomes yielded highly significant correlations between the formation of NPC and both immunoreactivity with anti-CYP3A antibodies and testosterone 6β-hydroxylation (an activity specifically mediated by CYP3A). The effects of 11 drugs (used at 100 μM) on this metabolism were studied with irinotecan lactone (25 μM). Although ondansetron, loperamide, and racecadotril inhibited this pathway by 75, 95, and 95%, respectively, the concentrations used may not be clinically achievable. However, significant inhibition by ketoconazole and troleandomycin indicates that NPC formation in patients may be influenced by coadministration of drugs with known anti-CYP3A activities.

Footnotes

  • Send reprint requests to: Dr. Jacques Robert, Institut Bergonié, 180 rue de Saint-Genès, 33076 Bordeaux Cedex, France.

  • This study was supported by grants from the Ligue Nationale Française contre le Cancer (Comité Départemental de Charente-Maritime), the Rhône-Poulenc Rorer Company, and the Pôle Médicament Aquitaine.

  • Abbreviations used are::
    CPT-11
    7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine
    SN-38
    7-ethyl-10-hydroxycamptothecine
    APC
    7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecine
    NPC
    7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine
    CYP
    cytochrome P450
    • Received January 6, 1998.
    • Accepted April 16, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 8
1 Aug 1998
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Research ArticleArticle

Biosynthesis of an Aminopiperidino Metabolite of Irinotecan [7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] by Human Hepatic Microsomes

Marie-Christine Haaz, Christian Riché, Laurent P. Rivory and Jacques Robert
Drug Metabolism and Disposition August 1, 1998, 26 (8) 769-774;

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Research ArticleArticle

Biosynthesis of an Aminopiperidino Metabolite of Irinotecan [7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] by Human Hepatic Microsomes

Marie-Christine Haaz, Christian Riché, Laurent P. Rivory and Jacques Robert
Drug Metabolism and Disposition August 1, 1998, 26 (8) 769-774;
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