title: Gastric damage in the rat with nitrogen-containing bisphosphonates depends on pH.
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.
  
  
  OBJECTIVE
  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.affiliation: Department of Drug Safety Assessment, Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Cincinnati, Ohio 45040, USA. blankma@pg.com
authors.forename: M A
authors.initials: MA
authors.lastname: Blank
authors.forename: G W
authors.initials: GW
authors.lastname: Gibson
authors.forename: W R
authors.initials: WR
authors.lastname: Myers
authors.forename: T A
authors.initials: TA
authors.lastname: Dierckman
authors.forename: R J
authors.initials: RJ
authors.lastname: Phipps
authors.forename: P N
authors.initials: PN
authors.lastname: Smith
mesh_terms: D000284:Administration, Oral; D019386:Alendronate / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D002121:Calcium Channel Blockers / Q000633:toxicity; D004164:Diphosphonates / Q000633:toxicity*; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000633:toxicity*; D008297:Male; D000077268:Pamidronate; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068296:Risedronic Acid; D013270:Stomach / Q000187:drug effects* / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D004164:Diphosphonates; D000068296:Risedronic Acid; D012968:Etidronic Acid; D000077268:Pamidronate; D019386:Alendronate; D007213:Indomethacin