title: Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea.
abstract: The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time (<2 h) was sufficient to induce these events. Because the decreased initial uptake of SN-38 carboxylate resulted in a reduced cellular toxicity, we postulated that the CPT-11-induced diarrhea was preventable by influencing the equilibrium toward the carboxylate form and, thus, reducing its intestinal uptake. In the golden Syrian hamster model, p.o. sodium bicarbonate supplementation (5 mg/ml in drinking water) led to alkalization of the intestinal contents. In addition, this alkalization resulted in the reduction of the histopathological damage to the mucosa of the small and large intestine, as well as a 20% reduction of the intestinal SN-38 lactone concentration of animals receiving CPT-11 (20-50 mg/kg x 7 days). Taken together, these results from in vitro and in vivo studies support intestinal alkalization by sodium bicarbonate supplementation as a preventive mechanism against CPT-11-induced diarrhea. In addition, this provides a strong rationale for the usage of this measure as an adjunct to CPT-11 treatment.
authors.affiliation: Department of Medicine, The George Washington University Medical Center, N. W. Washington, D.C. 20037, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ikegami
authors.forename: Linan
authors.initials: L
authors.lastname: Ha
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arimori
authors.forename: Patricia
authors.initials: P
authors.lastname: Latham
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Susan
authors.initials: S
authors.lastname: Ceryak
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Bernard
authors.initials: B
authors.lastname: Bouscarel
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000009:adverse effects / Q000493:pharmacokinetics; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D003967:Diarrhea / Q000139:chemically induced* / Q000517:prevention & control*; D020719:Glucuronides / Q000009:adverse effects / Q000493:pharmacokinetics; D019073:HT29 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000187:drug effects*; D000077146:Irinotecan; D007783:Lactones / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008647:Mesocricetus; D017693:Sodium Bicarbonate / Q000494:pharmacology*
chemical_list: C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000972:Antineoplastic Agents, Phytogenic; D002264:Carboxylic Acids; D020719:Glucuronides; D007783:Lactones; D000077146:Irinotecan; D017693:Sodium Bicarbonate; D002166:Camptothecin