PHARMACOKINETIC MODULATION OF IRINOTECAN AND METABOLITES BY CYCLOSPORINE-A

The focus of this investigation was to modulate the pharmacokinetics o f irinotecan and its metabolites, SN-38 and SN-38G, by possibly reduci ng biliary excretion, which in turn could lower irinotecan toxicity. W e determined the effect of a known cholestatic agent, cyclosporin A (C sA), which is transported across the bile canalicular membrane by P-gl ycoprotein, on the biliary excretion of irinotecan and its metabolites , Wistar rats were pretreated with 60 mg/kg CsA 5 min before an i.v. d ose of irinotecan at dose levels of 6, 10, and 20 mg/kg. The control g roups received irinotecan only, CsA pretreatment resulted in an averag e increase of 339, 361, and 192% in the area under the plasma concentr ation-time curve of irinotecan, SN-38, and SN-38G, respectively. Analy sis of clearance (CL) of irinotecan indicated a 55 and 81% reduction i n the average renal and nonrenal CLs, respectively, in the pretreated groups. The nonrenal CL, which is the primary component of irinotecan CL, includes protein and tissue binding as well as the metabolic and b iliary CL of irinotecan. There was no change in the volume of distribu tion at steady state (indicative of unchanged binding) and in the meta bolic conversion of irinotecan to SN-38 due to pretreatment. Therefore , the significant reduction in the systemic CL of irinotecan due to Cs A pretreatment was primarily due to lowered biliary excretion. Studies using a photoaffinity analogue of verapamil, [I-125]NAS-VP, and membr ane vesicles from the multidrug-resistant cell line, MCF-7/Adr, reveal ed that irinotecan and metabolites had moderate interaction with P-gly coprotein. Further studies are required to determine the mechanism of the inhibitory effect of CsA on the biliary excretion of irinotecan an d its metabolites.