RT Journal Article
SR Electronic
T1 Intestinal Transport of Irinotecan in Caco-2 Cells and MDCK II Cells Overexpressing Efflux Transporters Pgp, cMOAT, and MRP1
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 763
OP 770
DO 10.1124/dmd.30.7.763
VO 30
IS 7
A1 Feng R. Luo
A1 Pankaj V. Paranjpe
A1 Ailan Guo
A1 Eric Rubin
A1 Patrick Sinko
YR 2002
UL http://dmd.aspetjournals.org/content/30/7/763.abstract
AB Irinotecan (CPT-11) is a water-soluble camptothecin (CPT) derivative that has been recently approved in the United States for patients as a first-line therapy in advanced colorectal cancer. Phase I clinical trials using oral CPT-11 have shown poor and variable oral bioavailability. The present study was designed to investigate the intestinal absorption and efflux mechanisms of CPT-11 using in vitro cell culture models, Caco-2 cells, and engineered Madine-Darby canine kidney (MDCK) II cells overexpressing P-glycoprotein (Pgp), canalicular multispecific organic anion transporter (cMOAT), and multidrug resistance-associated protein (MRP1). The intestinal absorptive and secretory transport of CPT-11 was investigated using Caco-2 cell monolayers. Secretory transport was concentration-dependent and saturable. The secretory efflux permeability (Peff) of CPT-11 decreased with decreasing temperature, with an estimated activation energy of 19.6 ± 2.9 kcal/mol suggesting the involvement of active transporters. The involvement of potential secretory transporters was further characterized in MDCK II cells. The secretory efflux carrier permeability (Pc) was ∼4- and ∼2-fold greater in MDCK II/Pgp and MDCK II/cMOAT cells than that in MDCK II/wild-type cells. Furthermore, the secretory effluxPeff of CPT-11 was significantly decreased by Pgp inhibitors, elacridar (GF120918) (IC50 = 0.38 ± 0.06 μM) and verapamil (IC50 = 234 ± 48 μM) in MDCK II/Pgp cells and by cMOAT inhibitor 3-([{3-(2-[7-chloro-2-quinolinyl]ethyl)phenyl}-{(3-dimethylamino-3-oxoprphyl)-thio}-methyl]-thio) propanoic acid (MK571) (IC50 = 469 ± 60 μM) in MDCK II/cMOAT cells. Overall, the current study suggests that Pgp and cMOAT are capable of mediating the efflux of CPT-11 in vitro. Since both Pgp and cMOAT are expressed in the intestine, liver, and kidney, it is likely that these efflux transporters play a significant role limiting the oral absorption and disposition of this important anticancer drug. The American Society for Pharmacology and Experimental Therapeutics