M A Blank1, G W Gibson, W R Myers, T A Dierckman, R J Phipps, P N Smith. 1. Department of Drug Safety Assessment, Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Cincinnati, Ohio 45040, USA. blankma@pg.com
Abstract
BACKGROUND: The use of nitrogen-containing bisphosphonates (N-BPs) has been reported to be associated with gastrointestinal intolerance. The fasted, indomethacin-treated rat provides a model for assessing the gastrointestinal effects of these compounds. AIMS: The aims of this study were to elucidate the effect of pH on N-BP-induced gastric damage, and to evaluate the structure-activity relationship between N-BP anti-resorptive and gastric effects. METHODS: Fasted rats were dosed concomitantly with indomethacin (40 mg/kg, subcutaneously) and an N-BP (pamidronate, alendronate, or risedronate at 150 or 300 mg/kg, orally), with the N-BP dosing solutions adjusted to pH 2, 4 or 7. The aminopentane and aminohexane N-BPs (150, 225 or 300 mg/kg, orally) were only tested at pH 4 only. RESULTS: Nitrogen-containing bisphosphonate-induced gastric damage was pH-dependent, with increased damage at increasing pH. CONCLUSIONS: Gastric damage potential did not correlate with bone anti-resorptive effects, and the more potent anti-resorptive N-BPs were not necessarily more damaging to the stomach.
BACKGROUND: The use of nitrogen-containing bisphosphonates (N-BPs) has been reported to be associated with gastrointestinal intolerance. The fasted, indomethacin-treated rat provides a model for assessing the gastrointestinal effects of these compounds. AIMS: The aims of this study were to elucidate the effect of pH on N-BP-induced gastric damage, and to evaluate the structure-activity relationship between N-BP anti-resorptive and gastric effects. METHODS: Fasted rats were dosed concomitantly with indomethacin (40 mg/kg, subcutaneously) and an N-BP (pamidronate, alendronate, or risedronate at 150 or 300 mg/kg, orally), with the N-BP dosing solutions adjusted to pH 2, 4 or 7. The aminopentane and aminohexane N-BPs (150, 225 or 300 mg/kg, orally) were only tested at pH 4 only. RESULTS:Nitrogen-containing bisphosphonate-induced gastric damage was pH-dependent, with increased damage at increasing pH. CONCLUSIONS:Gastric damage potential did not correlate with bone anti-resorptive effects, and the more potent anti-resorptive N-BPs were not necessarily more damaging to the stomach.
Authors: Derek Lin; Jennifer R Kramer; David Ramsey; Abeer Alsarraj; Gordana Verstovsek; Massimo Rugge; Paola Parente; David Y Graham; Hashem B El-Serag Journal: Am J Gastroenterol Date: 2013-07-16 Impact factor: 10.864
Authors: Marcin Magierowski; Katarzyna Magierowska; Jakub Szmyd; Marcin Surmiak; Zbigniew Sliwowski; Slawomir Kwiecien; Tomasz Brzozowski Journal: Dig Dis Sci Date: 2016-08-19 Impact factor: 3.199