TY - JOUR
T1 - P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice.
AU - Tagen, Michael
AU - Zhuang, Yanli
AU - Zhang, Fan
AU - Harstead, K. Elaine
AU - Shen, Jun
AU - Schaiquevich, Paula
AU - Fraga, Charles H.
AU - Panetta, John C.
AU - Waters, Christopher M.
AU - Stewart, Clinton F.
PY - 2010/12/1
Y1 - 2010/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/79953306305
UR - https://www.scopus.com/pages/publications/79953306305#tab=citedBy
U2 - 10.2174/187231210792928251
DO - 10.2174/187231210792928251
M3 - Article
C2 - 20583968
AN - SCOPUS:79953306305
SN - 1872-3128
VL - 4
SP - 195
EP - 201
JO - Drug Metabolism Letters
JF - Drug Metabolism Letters
IS - 4
ER -