Involvement of specific transport system on uptake of lactone form of SN-38 in human intestinal epithelial cell line Caco-2.
The aim of this study was to elucidate the characteristics of the transport of lactone and carboxylate forms of SN-38 (SN-38L and SN-38C, respectively), a metabolite of irinotecan hydrochloride (CPT-11), with the human intestinal epithelial cell line, Caco-2. We examined SN-38L and SN-38C uptake from the apical side into Caco-2, and the effects of various compounds on the uptake of SN-38L. SN-38L and SN-38C in the cells were determined by HPLC with a fluorescence detector. When either SN-38L (0.5 µM) or SN-38C (0.5 µM) was added extracellularly at 37°C, the accumulation of SN-38L into the cells was about 10-fold higher than that of SN-38C, suggesting a dominant role of the lactone form in the uptake of SN-38 into Caco-2. The accumulation of SN-38L in Caco-2 increased time-dependently up to 10 min at 37°C, whereas the accumulation markedly decreased at 4°C. The initial uptake rate of SN-38L approached saturation at high concentrations with Michaelis-Menten constant and 'Hill coefficient,' 2.84±1.00 μM and 2.13±1.14, respectively (mean±S.E.). The accumulation of SN-38L was markedly inhibited by baicalin, an active ingredient of a Chinese herbal medicine, Hange-Shashin-To, as well as CPT-11. The type of inhibition by baicalin was competitive. In contrast, concomitant sulfobromophthalein, taurocholate and estrone 3-sulfate significantly increased SN-38L uptake. These results suggest that apical uptake of SN-38 by Caco-2 is dominantly performed as a lactone form through a specific transporter, which is competitively inhibited by baicalin.
Department of Clinical Pharmacy and Biopharmaceutics, Graduate School of Medicine, Mie University, Edobashi, Tsu, Mie 514–8507, Japan.
Yusuke
Y
Ueno
Hiroko
H
Matsuda
Hideki
H
Mizutani
Takuya
T
Iwamoto
Masahiro
M
Okuda
D001692:Biological Transport; D018938:Caco-2 Cells; D029769:Camptotheca / Q000737:chemistry*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D004970:Estrone / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D000077146:Irinotecan; D007783:Lactones / Q000378:metabolism*; D013448:Sulfobromophthalein / Q000494:pharmacology; D013656:Taurocholic Acid / Q000494:pharmacology
D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D007783:Lactones; D013448:Sulfobromophthalein; D004970:Estrone; C038044:baicalin; D013656:Taurocholic Acid; D000077146:Irinotecan; D002166:Camptothecin