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pH‐dependent uptake of irinotecan and its active metabolite, SN‐38, by intestinal cells
Author(s) -
Kobayashi Kunihiko,
Bouscarel Bernard,
Matsuzaki Yasushi,
Ceryak Susan,
Kudoh Shoji,
Fromm Hans
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19991112)83:4<491::aid-ijc10>3.0.co;2-m
Subject(s) - sn 38 , cytotoxicity , metabolite , chemistry , carboxylate , active metabolite , biochemistry , irinotecan , absorption (acoustics) , in vitro , medicine , physics , colorectal cancer , cancer , acoustics
Irinotecan (CPT‐11) and its active metabolite, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), are believed to be reabsorbed by intestinal cells and to enter the entero‐hepatic circulation, but there is little information to date. Our objective was to investigate the intestinal transport of CPT‐11 and SN‐38 in correlation with their associated cytotoxicity. Using either isolated hamster intestinal epithelial cells or/and human colon carcinoma HT29 cells, the uptake rates of [ 14 C]CPT‐11 and [ 14 C]SN‐38, both as respective non‐ionic lactone form at acidic pH and anionic carboxylate form at basic pH, were investigated by the rapid vacuum filtration technique. The effect of physiologic intestinal luminal pH (6.2–8.0) on the uptake rate and cytotoxicity of SN‐38 were estimated by the above method and the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐tetrazolium bromide (MTT) assay, respectively. The lactone forms of CPT‐11 and SN‐38 were transported passively, while the respective carboxylate form was absorbed actively. Uptake rates of both lactones were significantly higher than those of their carboxylates. Under physiologic pH, the respective uptake rates of CPT‐11 and SN‐38 were pH sensitive and decreased significantly by around 65%, at pH greater than 6.8. Furthermore, with decreasing pH, a higher uptake rate of SN‐38 into HT29 cells correlates with a greater cytotoxic effect (r = 0.987). CPT‐11 and SN‐38 have absorption characteristics of weakly basic drugs such as short‐chain fatty acids, suggesting that alkalization of the intestinal lumen may be critical to reduce their reabsorption and associated side effects. Int. J. Cancer 83:491–496, 1999. © 1999 Wiley‐Liss, Inc.