Effect of P-glycoprotein modulator, cyclosporin A, on the gastrointestinal excretion of irinotecan and its metabolite SN-38 in rats.
OBJECTIVE
The purpose of this work was to investigate the role of the hepatic and intestinal P-glycoprotein (P-gp) and canalicular multispecific organic anion transporter/multidrug resistance-associated protein 2 (cMOAT/MRP2) on both biliary excretion and intestinal exsorption of irinotecan hydrochloride (CPT-11) and its metabolite, SN-38, in the lactone and carboxylate forms. Cyclosporin A (CsA) was used to modulate P-gp and cMOAT/MRP2.


METHODS
The transcellular transport of CPT-11 and SN-38 was examined by using LLC-PK1 derivative cell lines transfected with murine mdrla both in the absence or in the presence of CsA. The excretions of the compounds through the biliary and intestinal membrane routes were investigated by in situ perfusion technique.


RESULTS
Basolateral-to-apical transport of CPT-11 lactone in L-mdr1a cells was significantly decreased by CsA (10 microM). The transcellular transport of SN-38 lactone showed similar behaviors as those of CPT-11 lactone. The biliary excretion and the intestinal exsorption of both forms of CPT-11 and SN-38 were significantly inhibited when the drug was co-administered with CsA.


CONCLUSIONS
The transports of CPT-11 and SN-38 via the biliary route seem to be essentially related with cMOAT/MRP2, whereas those of both compounds via the intestinal membrane seem to be related with P-gp.
Arimori
Kazuhiko
K
Department of Pharmacy, Miyazaki Medical College, 5200 Kihara, Kiyotake-cho, Miyazaki-gun, Miyazaki 889-1692, Japan. arimori@post.miyazaki-med.ac.jp
Kuroki
Noriaki
N
Hidaka
Muneaki
M
Iwakiri
Tomomi
T
Yamsaki
Keishi
K
Okumura
Manabu
M
Ono
Hiroshige
H
Takamura
Norito
N
Kikuchi
Masahiko
M
Nakano
Masahiro
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000494:pharmacology*; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D000077146:Irinotecan; D018374:LLC-PK1 Cells; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014018:Tissue Distribution
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D000077146:Irinotecan; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C095122:multidrug resistance protein 3