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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
|
| pubmed:dateCreated |
1998-2-24
|
| pubmed:abstractText |
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 microM; 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 microM) and troleandomycin (100 microM) 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 6beta hydroxylation, an activity specifically mediated by CYP 3A. The effect on this metabolism of 11 drugs used at 100 microM was studied with CPT-11 lactone at 25 microM. 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.
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| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Phytogenic,
http://linkedlifedata.com/resource/pubmed/chemical/Aryl Hydrocarbon Hydroxylases,
http://linkedlifedata.com/resource/pubmed/chemical/Camptothecin,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 CYP3A,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Ketoconazole,
http://linkedlifedata.com/resource/pubmed/chemical/Oxidoreductases, N-Demethylating,
http://linkedlifedata.com/resource/pubmed/chemical/RPR 121056,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Troleandomycin,
http://linkedlifedata.com/resource/pubmed/chemical/irinotecan
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Feb
|
| pubmed:issn |
0008-5472
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
1
|
| pubmed:volume |
58
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
468-72
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:9458091-Antineoplastic Agents, Phytogenic,
pubmed-meshheading:9458091-Aryl Hydrocarbon Hydroxylases,
pubmed-meshheading:9458091-Biotransformation,
pubmed-meshheading:9458091-Camptothecin,
pubmed-meshheading:9458091-Cytochrome P-450 CYP3A,
pubmed-meshheading:9458091-Cytochrome P-450 Enzyme System,
pubmed-meshheading:9458091-Drug Interactions,
pubmed-meshheading:9458091-Enzyme Inhibitors,
pubmed-meshheading:9458091-Humans,
pubmed-meshheading:9458091-Ketoconazole,
pubmed-meshheading:9458091-Microsomes, Liver,
pubmed-meshheading:9458091-Molecular Structure,
pubmed-meshheading:9458091-Oxidoreductases, N-Demethylating,
pubmed-meshheading:9458091-Recombinant Proteins,
pubmed-meshheading:9458091-Structure-Activity Relationship,
pubmed-meshheading:9458091-Transfection,
pubmed-meshheading:9458091-Troleandomycin
|
| pubmed:year |
1998
|
| pubmed:articleTitle |
Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions.
|
| pubmed:affiliation |
Institut Bergonié and Université Victor Segalen Bordeaux 2, France.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|