Abstract
Irinotecan, or CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine), is a water-soluble derivative of camptothecine with promising activity against several types of malignancies. In addition to 7-ethyl-10-hydroxycamptothecine (SN-38), its active metabolite, we were able to identify several metabolites in the plasma of patients treated with this drug, especially an oxidative metabolite, 7-ethyl-10[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecine. During our study of the biosynthesis of 7-ethyl-10[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecine from CPT-11 by human liver microsomes, we were able to detect another quantitatively important polar metabolite, which was also present in the plasma and urine of patients treated with CPT-11. On the basis of preliminary experiments, the structure of this compound was postulated to be 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine, and this structure was synthesized by Rhône-Poulenc Rorer. Urine samples and human liver microsomal extracts were studied by high-performance liquid chromatography/atmospheric pressure chemical ionization/tandem mass spectrometry to identify its structure formally. The identification of the metabolite was supported by identical retention time, mass-to-charge ratio and tandem mass spectrometry fragmentation as a synthetic standard. Like irinotecan, 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecine was a weak inhibitor of cell growth of P388 cells in culture (IC50 = 3.4 μg/ml vs. 2.8 μg/ml for irinotecan and 0.001 μg/ml for SN-38). It was also a poor inducer of topoisomerase I-DNA cleavable complexes (100-fold less potent than SN-38). However, unlike 7-ethyl-10[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecine, this new metabolite could be hydrolyzed to SN-38 by human liver microsomes and purified human liver carboxylesterase, though to a lesser extent than irinotecan. This compound can therefore contribute to the activity and toxicity profile of irinotecan in vivo.
Footnotes
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Send reprint requests to: Jacques Robert, Dr. Med., Dr. Sci., Institut Bergonié, 180 rue de Saint-Genès, 33076 Bordeaux-cedex, France.
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↵1 This study was supported by grants from the Ligue Nationale Française contre le Cancer, the Rhône-Poulenc Rorer company and the Princess Alexandra Hospital Research Foundation.
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↵2 Present address: Cancer Pharmacology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia.
- Abbreviations:
- APCI
- atmospheric pressure chemical ionization
- MS
- mass spectrometry
- 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]carbonyloxy-camptothecine
- NPC
- 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine
- CYP
- cytochrome P-450
- m/z
- mass-to-charge ratio
- SDS
- sodium dodecyl sulfate
- PBS
- phosphate-buffered saline
- topo I
- topoisomerase I
- Received January 7, 1998.
- Accepted March 30, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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