This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rivory, L. P. Articles by Robert, J. Search for Related Content PubMed PubMed Citation Articles by Rivory, L. P. Articles by Robert, J.

Kinetics of the in Vivo Interconversion of the Carboxylate and Lactone Forms of Irinotecan (CPT-11) and of Its Metabolite SN-38 in Patients¹

Université de Bordeaux II, 146 rue Léo Saignat [L. P. R., J. R.]; Fondation Bergonié, 180 rue de Saint-Genès [L. P. R., J. R.] Bordeaux-Cedex 33076; Centre Claudius Regaud, 20 rue du Pont St.-Pierre, Toulouse-Cedex 31052 [E. C., P. C.]; and Bellon, Rhône-Poulenc Rorer, 159 avenue Achille Peretti, Neuilly-Cedex 92201 [A. M-B.], France

The kinetics of the in vivo interconversion of the carboxylate and lactone forms of the prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), and its active metabolite SN-38 were studied in five patients using a HPLC method that allows the simultaneous determination of all four compounds and detects any hydrolysis of lactones due to inadequate sample handling and storage. The apparent conversion of CPT-11 lactone to the carboxylate in vivo was rapid with a mean half-life of 9.5 min; the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the area under the plasma concentration-time curves of the lactone to total CPT-11 was 36.8 ± 3.5% (SD). In contrast, SN-38 was present predominantly as the lactone at all times and with little interpatient variability (lactone/total area under the plasma concentration-time curve ratio, 64.0 ± 3.4%). This may explain in part the promising activity of CPT-11 because CPT derivatives are active against their target, topoisomerase I, only in their lactone form.

¹ Supported in part by the Association pour la Recherche sur le Cancer (France) and the Groupement des Entreprises Françaises dans la Lutte Contre le Cancer. L. P. R. is the reçipient of a NHMRC/INSERM Exchange Fellowship.

² To whom requests for reprints should be addressed, at Département de Biochimie Médicale, Université de Bordeaux II, 146 rue Léo Saignat, Bordeaux Cedex, 33076 France.

Received 9/26/94. Accepted 11/ 3/94.

This article has been cited by other articles:

				K. Yokoo, A. Hamada, H. Watanabe, T. Matsuzaki, T. Imai, H. Fujimoto, K. Masa, T. Imai, and H. Saito Involvement of Up-Regulation of Hepatic Breast Cancer Resistance Protein in Decreased Plasma Concentration of 7-Ethyl-10-hydroxycamptothecin (SN-38) by Coadministration of S-1 in Rats Drug Metab. Dispos., September 1, 2007; 35(9): 1511 - 1517. [Abstract] [Full Text] [PDF]

				M. N. Tallman, J. K. Ritter, and P. C. Smith DIFFERENTIAL RATES OF GLUCURONIDATION FOR 7-ETHYL-10-HYDROXY-CAMPTOTHECIN (SN-38) LACTONE AND CARBOXYLATE IN HUMAN AND RAT MICROSOMES AND RECOMBINANT UDP-GLUCURONOSYLTRANSFERASE ISOFORMS Drug Metab. Dispos., July 1, 2005; 33(7): 977 - 983. [Abstract] [Full Text] [PDF]

				S. Poujol, F. Pinguet, F. Malosse, C. Astre, M. Ychou, S. Culine, and F. Bressolle Sensitive HPLC-Fluorescence Method for Irinotecan and Four Major Metabolites in Human Plasma and Saliva: Application to Pharmacokinetic Studies Clin. Chem., November 1, 2003; 49(11): 1900 - 1908. [Abstract] [Full Text] [PDF]

				K. J. P. Yoon, E. J. Krull, C. L. Morton, W. G. Bornmann, R. E. Lee, P. M. Potter, and M. K. Danks Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies Mol. Cancer Ther., November 1, 2003; 2(11): 1171 - 1181. [Abstract] [Full Text] [PDF]

				N. Kemeny, W. Tong, M. Gonen, J. Stockman, C. Di Lauro, J. Teitcher, P. White, C. Price, L. Saltz, S. Sharma, et al. Phase I study of weekly oxaliplatin plus irinotecan in previously treated patients with metastatic colorectal cancer Ann. Onc., September 1, 2002; 13(9): 1490 - 1496. [Abstract] [Full Text] [PDF]

				R. Xie, R. H.J. Mathijssen, A. Sparreboom, J. Verweij, and M. O. Karlsson Clinical Pharmacokinetics of Irinotecan and Its Metabolites: A Population Analysis J. Clin. Oncol., August 1, 2002; 20(15): 3293 - 3301. [Abstract] [Full Text] [PDF]

				G. Xu, W. Zhang, M. K. Ma, and H. L. McLeod Human Carboxylesterase 2 Is Commonly Expressed in Tumor Tissue and Is Correlated with Activation of Irinotecan Clin. Cancer Res., August 1, 2002; 8(8): 2605 - 2611. [Abstract] [Full Text] [PDF]

				T. Ikegami, L. Ha, K. Arimori, P. Latham, K. Kobayashi, S. Ceryak, Y. Matsuzaki, and B. Bouscarel Intestinal Alkalization As a Possible Preventive Mechanism in Irinotecan (CPT-11)-induced Diarrhea Cancer Res., January 1, 2002; 62(1): 179 - 187. [Abstract] [Full Text] [PDF]

				R. H. J. Mathijssen, R. J. van Alphen, J. Verweij, W. J. Loos, K. Nooter, G. Stoter, and A. Sparreboom Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11) Clin. Cancer Res., August 1, 2001; 7(8): 2182 - 2194. [Abstract] [Full Text] [PDF]

				U. Vanhoefer, A. Harstrick, W. Achterrath, S. Cao, S. Seeber, and Y. M. Rustum Irinotecan in the Treatment of Colorectal Cancer: Clinical Overview J. Clin. Oncol., March 1, 2001; 19(5): 1501 - 1518. [Abstract] [Full Text] [PDF]

				S. Blaney, S. L. Berg, C. Pratt, S. Weitman, J. Sullivan, L. Luchtman-Jones, and M. Bernstein A Phase I Study of Irinotecan in Pediatric Patients: A Pediatric Oncology Group Study Clin. Cancer Res., January 1, 2001; 7(1): 32 - 37. [Abstract] [Full Text]

				J. Thiesen and I. Kramer Physicochemical stability of irinotecan injection concentrate and diluted infusion solutions in PVC bags Journal of Oncology Pharmacy Practice, September 1, 2000; 6(3): 115 - 121. [Abstract] [PDF]

				M. J. A. de Jonge, J. Verweij, P. de Bruijn, E. Brouwer, R. H. J. Mathijssen, R. J. van Alphen, M. M. de Boer-Dennert, L. Vernillet, C. Jacques, and A. Sparreboom Pharmacokinetic, Metabolic, and Pharmacodynamic Profiles in a Dose-Escalating Study of Irinotecan and Cisplatin J. Clin. Oncol., January 5, 2000; 18(1): 195 - 195. [Abstract] [Full Text] [PDF]

				H. M. Dodds and L. P. Rivory The Mechanism for the Inhibition of Acetylcholinesterases by Irinotecan (CPT-11) Mol. Pharmacol., December 1, 1999; 56(6): 1346 - 1353. [Abstract] [Full Text]

				D. A. Nicoll-Griffith, J.-P. Falgueyret, J. M. Silva, P.-E. Morin, L. Trimble, C.-C. Chan, S. Clas, S. Leger, Z. Wang, J. A. Yergey, et al. Oxidative Bioactivation of the Lactol Prodrug of A Lactone Cyclooxygenase-2 Inhibitor Drug Metab. Dispos., March 1, 1999; 27(3): 403 - 409. [Abstract] [Full Text]

				J. A. Skirvin and V. Relias Review : Topoisomerase I inhibitors: 2. Irinotecan Journal of Oncology Pharmacy Practice, June 1, 1998; 4(2): 103 - 116. [Abstract] [PDF]