The sugar absorption test in the evaluation of the gastrointestinal intolerance to bisphosphonates: studies with oral pamidronate.
RATIONALE AND AIMS Some bisphosphonates induce gastrointestinal side effects, but the localization in the gastrointestinal tract and the underlying mechanism are unknown. The feasibility of the sugar absorption test was investigated to assess the gastrointestinal effects of oral enteric-coated pamidronate. The sugar absorption test measures the urinary excretion of lactulose, mannitol, and sucrose after oral intake. Increases in the lactulose/mannitol ratio and sucrose excretion indicate increased small intestinal permeability and gastroduodenal disease, respectively.


METHODS
Twelve volunteers (5 women and 7 men) participated in a randomized, double-blind, 4-way crossover study. The sugar absorption test was performed 2 hours after the final drug intake following a 3-day course of enteric-coated pamidronate (300 mg daily), placebo, or acetylsalicylic acid (3 g daily). The lactulose/mannitol ratio and sucrose excretion were measured in urine collected for 5 hours after ingestion of the solution. The fourth treatment consisted of intravenous administration of pamidronate. Treatment comparison was with paired t tests after log-transformation.


RESULTS
The lactulose/mannitol ratio after pamidronate and acetylsalicylic acid administration was 54% and 118% higher than that after placebo (95% confidence intervals [CI], +8%, +119%, and +69%, +182%). The lactulose/mannitol ratio after pamidronate administration was 29% lower (95% CI, -54%, +3%) than that after acetylsalicylic acid. Compared with placebo the sucrose excretion was 290% higher after acetylsalicylic acid (95% CI, +46%, +518%) but only 8% higher after pamidronate (95% CI, -41%, +97%). The absorption of pamidronate was below 1%, and there was no relationship with the increased lactulose/mannitol ratio.


CONCLUSIONS
Oral enteric-coated pamidronate increases intestinal but not gastroduodenal permeability. There was no relationship between intestinal permeability and absorption of pamidronate. It appears that the sugar absorption test is an appropriate, noninvasive method for evaluation of gastrointestinal effects of bisphosphonates in humans.
Twiss
I M
IM
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. IMTeepe-Twiss@lumc.nl
Burggraaf
J
J
Schoemaker
R C
RC
van Elburg
R M
RM
den Hartigh
J
J
Cohen
A F
AF
Vermeij
P
P
D000042:Absorption; D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D019540:Area Under Curve; D001241:Aspirin / Q000493:pharmacokinetics; D001682:Biological Availability; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000652:urine; D018592:Cross-Over Studies; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D004311:Double-Blind Method; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced*; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D000077268:Pamidronate; D013608:Tablets, Enteric-Coated
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002241:Carbohydrates; D004164:Diphosphonates; D013608:Tablets, Enteric-Coated; D000077268:Pamidronate; D001241:Aspirin