title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tagen
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhuang
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: K Elaine
authors.initials: KE
authors.lastname: Harstead
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Paula
authors.initials: P
authors.lastname: Schaiquevich
authors.forename: Charles H
authors.initials: CH
authors.lastname: Fraga
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000097:blood; D005260:Female; D005838:Genotype; D007275:Injections, Intravenous; D000077146:Irinotecan; D007783:Lactones / Q000097:blood; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D002166:Camptothecin; D002264:Carboxylic Acids; D000077146:Irinotecan; D007783:Lactones; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C073492:ABCC4 protein, human; C095122:multidrug resistance protein 3