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Clinical Cancer Research Vol. 7, 2182-2194, August 2001
© 2001 American Association for Cancer Research

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Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11)

Ron H. J. Mathijssen1, Robbert J. van Alphen1, Jaap Verweij, Walter J. Loos, Kees Nooter, Gerrit Stoter and Alex Sparreboom2

Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3008 AE Rotterdam, the Netherlands

CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100–1000-fold more cytotoxic than the parent drug. CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types including colorectal, lung, cervical, and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which an equilibrium exists that depends on the pH and the presence of binding proteins. CPT-11 is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects are under way and may ultimately lead to more selective chemotherapeutic use of this agent.




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