PHARMACOLOGY OF IRINOTECAN

Irinotecan (CPT-II) is a semisynthetic derivative of camptothecin, an alkaloid extracted from the Chinese plant Camptotheca acuminata. It be ars a bis-piperidine moiety and was selected for its water solubility and promising preclinical antitumor activity in in vitro and in vivo m odels. The target of drugs of the camptothecin family is DNA topoisome rase I, a nuclear enzyme involved in the relaxation of the DNA double helix required for replication and transcription activities. They stab ilize the enzyme-DNA complex and prevent the religation of the single- strand breaks created by the enzyme, which are converted to double-str and breaks upon the collision with a replication fork during the S-pha se. Resistance to irinotecan appears not to be mediated by P-glycoprot ein, but by qualitative and/or quantitative alterations of its target, topoisomerase I, or by alterations occurring downstream of this inter action. As with all camptothecin derivatives, irinotecan contains a la ctone ring that can be spontaneously and reversibly hydrolyzed to a ca rboxylate open ring form, which predominates at neutral and alkaline p H and is inactive on topoisomerase I-DNA complexes. Irinotecan is, in fact, much less active than its metabolite SN-38 and is generally cons idered as a prodrug of this compound. The carboxylesterase which carri es out this conversion is preferentially active on the lactone form of irinotecan and directly generates the lactone form of SN-38, which ma y explain the superiority of irinotecan over SN-38 in vivo. Further me tabolism of SN-38 to a beta-glucuronide conjugate is a major pathway o f detoxification and plays an important role in determining irinotecan toxicity in the clinical setting. Other metabolic pathways of irinote can involve oxidations occurring on the bis-piperidine rings, which ar e carried out by cytochrome P450. Irinotecan has shown an important ac tivity in advanced and metastatic colorectal carcinoma and is now used for this indication in several countries, with two different recommen ded schedules: weekly administration of 125 mg/m(2) with a 2-week drug -free interval every 4 administrations or 3-weekly administration of 3 50 mg/m(2), a dose that can be increased to 500 mg/m(2) with the suppo rt of antidiarrhetics. Other possible indications of irinotecan includ e lung and cervix cancer, which are presently under investigation. The dose-limiting toxicity of irinotecan is mainly diarrhea, which occurs 7-10 days after treatment and can be life-threatening when associated with neutropenia, another frequent side effect. High-dose loperamide has shown good efficacy for treating this diarrhea and has allowed an increase in irinotecan doses tolerated by patients. The pharmacokineti cs of irinotecan are characterized by a 2- or 3-compartment decay, wit h a terminal half-life of about 10 h, a total volume of distribution o f 150 l/m(2) and a total plasma clearance of 15 l/h/m(2). SN-38 AUC is only a small fraction of that of irinotecan (2-4%) and SN-38 is elimi nated from plasma with a half-life of about 12 h. SN-38 glucuronide is present in plasma at higher concentrations than SN-38 and is eliminat ed at the same rate. APC, produced by the action of cytochrome P450, i soenzyme 3A4, is present in plasma at concentrations close to those of irinotecan itself. Only a small fraction of irinotecan and its metabo lites is eliminated in urine and a higher proportion in the bile, with an enterohepatic cycle of SN-38 glucuronide and SN-38. Significant re lationships have been established between the AUCs of both irinotecan and SN-38 and hematological and intestinal toxicities, suggesting a po tential use for monitoring of this drug, (C) 1998 Prous Science. All l ights reserved.