Pharmacokinetic modulation of irinotecan and metabolites by cyclosporin A.
The focus of this investigation was to modulate the pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G, by possibly reducing biliary excretion, which in turn could lower irinotecan toxicity. We determined the effect of a known cholestatic agent, cyclosporin A (CsA), which is transported across the bile canalicular membrane by P-glycoprotein, on the biliary excretion of irinotecan and its metabolites. Wistar rats were pretreated with 60 mg/kg CsA 5 min before an i.v. dose of irinotecan at dose levels of 6, 10, and 20 mg/kg. The control groups received irinotecan only. CsA pretreatment resulted in an average increase of 339, 361, and 192% in the area under the plasma concentration-time curve of irinotecan, SN-38, and SN-38G, respectively. Analysis of clearance (CL) of irinotecan indicated a 55 and 81% reduction in 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 biliary CL of irinotecan. There was no change in the volume of distribution at steady state (indicative of unchanged binding) and in the metabolic conversion of irinotecan to SN-38 due to pretreatment. Therefore, the significant reduction in the systemic CL of irinotecan due to CsA pretreatment was primarily due to lowered biliary excretion. Studies using a photoaffinity analogue of verapamil, [125I]NAS-VP, and membrane vesicles from the multidrug-resistant cell line, MCF-7/Adr, revealed that irinotecan and metabolites had moderate interaction with P-glycoprotein. Further studies are required to determine the mechanism of inhibitory effect of CsA on the biliary excretion of irinotecan and its metabolites.
Gupta
E
E
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Illinois 60637, USA.
Safa
A R
AR
Wang
X
X
Ratain
M J
MJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000187:drug effects* / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D000077146:Irinotecan; D051381:Rats; D017208:Rats, Wistar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D016572:Cyclosporine; D002166:Camptothecin