Involvement of Up-Regulation of Hepatic Breast Cancer Resistance Protein in Decreased Plasma Concentration of 7-Ethyl-10-hydroxycamptothecin (SN-38) by Coadministration of S-1 in Rats

Abstract

The safety and efficacy of combination therapy with 7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycamptothecin (CPT-11, irinotecan) and S-1 composed of tegafur, a prodrug of 5-fluorouracil, gimeracil, and potassium oxonate, have been confirmed in patients with colorectal cancer. Previously, we showed that p.o. coadministration of S-1 decreased the plasma concentration of both CPT-11 and its metabolites in a patient with advanced colorectal cancer. The aim of this study was to clarify the mechanism of drug interaction using both in vivo and in vitro methods. Rats were administered S-1 p.o. (10 mg/kg) once a day for 7 consecutive days. On day 7, CPT-11 (10 mg/kg) was administered by i.v. injection. Coadministration of S-1 affected the pharmacokinetic behavior of CPT-11 and its metabolites, with a decrease in the C(max) and area under the plasma concentration curve (AUC) of the active metabolite 7-ethyl-10-hydroxycampothecin (SN-38) lactone form. Furthermore, the rate of biliary excretion of the SN-38 carboxylate form increased on coadministration of S-1. In the liver, the level of breast cancer resistance protein (BCRP), but not P-glycoprotein and multidrug resistance-associated protein 2, was elevated after administration of S-1. Enzymatic conversion of CPT-11 to SN-38 by carboxylesterase (CES) was unaffected by the liver microsomes of rats treated with S-1. In addition, components of S-1 did not inhibit the hydrolysis of p-nitrophenylacetate, a substrate of CES, in the S9 fraction of HepG2 cells. Therefore, the mechanism of drug interaction between CPT-11 and S-1 appears to involve up-regulation of BCRP in the liver, resulting in an increased rate of biliary excretion of SN-38 accompanied by a decrease in the C(max) and AUC of SN-38.