Arimori Kazuhiko, Kuroki Noriaki, Hidaka Muneaki, Iwakiri Tomomi, Yamsaki Keishi, Okumura Manabu, Ono Hiroshige, Takamura Norito, Kikuchi Masahiko, Nakano Masahiro
Department of Pharmacy, Miyazaki Medical College, 5200 Kihara, Kiyotake-cho, Miyazaki-gun, Miyazaki 889-1692, Japan.
Pharm Res. 2003 Jun;20(6):910-7. doi: 10.1023/a:1023847521767.
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.
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.
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.
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.
本研究旨在探讨肝脏和肠道中的P-糖蛋白（P-gp）以及胆小管多特异性有机阴离子转运体/多药耐药相关蛋白2（cMOAT/MRP2）在盐酸伊立替康（CPT-11）及其代谢产物SN-38内酯型和羧酸盐型的胆汁排泄及肠道重吸收中的作用。使用环孢素A（CsA）调节P-gp和cMOAT/MRP2。
利用转染了小鼠mdrla的LLC-PK1衍生细胞系，在不存在或存在CsA的情况下检测CPT-11和SN-38的跨细胞转运。通过原位灌注技术研究化合物经胆汁和肠膜途径的排泄情况。
CsA（10微摩尔）显著降低了L-mdr1a细胞中CPT-11内酯从基底外侧到顶端的转运。SN-38内酯的跨细胞转运表现出与CPT-11内酯相似的行为。当药物与CsA共同给药时，CPT-11和SN-38两种形式的胆汁排泄和肠道重吸收均受到显著抑制。
CPT-11和SN-38经胆汁途径的转运似乎主要与cMOAT/MRP2有关，而这两种化合物经肠膜的转运似乎与P-gp有关。
