Gastric damage in the rat with nitrogen-containing bisphosphonates depends on pH.
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.
Blank
M A
MA
Department of Drug Safety Assessment, Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Cincinnati, Ohio 45040, USA. blankma@pg.com
Gibson
G W
GW
Myers
W R
WR
Dierckman
T A
TA
Phipps
R J
RJ
Smith
P N
PN
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D004164:Diphosphonates; D000068296:Risedronic Acid; D012968:Etidronic Acid; D000077268:Pamidronate; D019386:Alendronate; D007213:Indomethacin