P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice

Abstract

The ATP-binding cassette transporters P-glycoprotein (ABCB1, MDR1) and multidrug resistance protein 4 (MRP4) efflux irinotecan and its active metabolite SN-38 in vitro, and thus may contribute to system clearance of these compounds. Mdr1a/b(-/-), Mrp4(-/-), and wild-type mice were administered 20 or 40 mg/kg irinotecan, and plasma samples were collected for 6 hours. Irinotecan and SN-38 lactone and carboxylate were quantitated and data were analyzed with nonlinear mixed-effects modeling. Mdr1a/b genotype was a significant covariate for the clearance of both irinotecan lactone and SN-38 lactone. Exposures to irinotecan lactone and SN-38 lactone after a 40 mg/kg dose were 1.6-fold higher in Mdr1a/b(-/-) mice compared to wild-type mice. Plasma concentrations of irinotecan lactone, irinotecan carboxylate, and SN-38 lactone in Mrp4(-/-) mice were similar to the wild-type controls. These results suggest that P-gp plays a role in irinotecan and SN-38 elimination, but Mrp4 does not affect irinotecan or SN-38 plasma pharmacokinetics.

Figure 1

The four-compartment model for irinotecan lactone (L), irinotecan carboxylate (C), and SN-38 L. Irinotecan lactone is administered as an i.v. bolus into the central compartment. Irinotecan lactone and carboxylate are in an equilibrium described by the parameters CL_LacCarb and CL_CarbLac. Irinotecan lactone is converted to SN-38 lactone by the apparent clearance, CL_IRN/ FE, where FE is the fraction of irinotecan lactone converted to SN-38 lactone. There is both a central and peripheral compartment for SN-38 lactone with clearance (CL_SN) occurring from the central compartment.

Figure 2

Concentration-time profile of plasma irinotecan and SN-38 in Mdr1a/b^−/− and wild-type mice. Plasma irinotecan lactone (A), irinotecan carboxylate (B), and SN-38 lactone (C) concentration-time data after 20 mg/kg (left column) and 40 mg/kg (right colunn) irinotecan intravenous injection. Symbols represent individual concentration-time points and the line represents the population-predicted values from the final pharmacokinetic model for Mdr1a/b^−/− and wild-type mice. Each group consisted of 5-6 mice.

Figure 3

Concentration-time profile of plasma irinotecan and SN-38 in Mrp4^−/− and wild-type mice. Plasma irinotecan lactone (A), irinotecan carboxylate (B), and SN-38 lactone (C) concentration-time data after 20 mg/kg (left column) and 40 mg/kg (right colunn) irinotecan intravenous injection. Symbols represent individual concentration-time points, and the line represents the population-predicted values from the final pharmacokinetic model of wild-type and Mrp4^−/− mice. Only one line is seen because Mrp4^−/− genotype was not a significant covariate on any pharmacokinetic parameter. Each group consisted of 6-7 mice.