Pharmacokinetic Modulation of Irinotecan and Metabolites by Cyclosporin A

摘要: The focus of this investigation was to modulate the pharmacokinetics irinotecan and its metabolites, SN-38 SN-38G, by possibly reducing biliary excretion, which in turn could lower toxicity. We determined effect a known cholestatic agent, cyclosporin A (CsA), is transported across bile canalicular membrane P-glycoprotein, on excretion metabolites. Wistar rats were pretreated with 60 mg/kg CsA 5 min before an i.v. dose at levels 6, 10, 20 mg/kg. control groups received only. pretreatment resulted average increase 339, 361, 192% area under plasma concentration-time curve irinotecan, SN-38, respectively. Analysis clearance (CL) indicated 55 81% reduction renal nonrenal CLs, respectively, groups. CL, primary component includes protein tissue binding as well metabolic CL irinotecan. There no change volume distribution steady state (indicative unchanged binding) conversion due pretreatment. Therefore, significant systemic primarily lowered excretion. Studies using photoaffinity analogue verapamil, [125I]NAS-VP, vesicles from multidrug-resistant cell line, MCF-7/Adr, revealed that metabolites had moderate interaction P-glycoprotein. Further studies are required determine mechanism inhibitory