P-glycoprotein, but not Multidrug Resistance Protein 4, Plays a Role in the Systemic Clearance of Irinotecan and SN-38 in Mice.

TAGEN M; ZHUANG Y; ZHANG F; HARSTEAD KE; SHEN J; SCHAIQUEVICH P; FRAGA CH; PANETTA JC; WATERS CM; STEWART CF

Drug metabolism lett

BENTHAM SCIENCE PUBL LTD

Año: 2010 vol. 4 p. 195 - 201

1872-3128

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.