Co-administration of misoprostol or ranitidine with indomethacin: effects on pharmacokinetics, abdominal symptoms and bowel habit.
This three-way randomized crossover study in 18 healthy male volunteers compared the pharmacokinetics of 50 mg indomethacin b.d. during concomitant twice daily dosing with 400 micrograms misoprostol, 150 mg ranitidine or placebo. Plasma indomethacin concentrations were determined by HPLC assay of samples collected over 12 h after the first dose, and over 14 h after the last dose on Day 8 of each dosing period. A daily diary of bowel habits, and the occurrence and severity of abdominal symptoms, was kept by each subject throughout the study. Statistical comparisons were made by analysis of variance. In the presence of misoprostol there was a 13% decrease in the area under the plasma concentration-time curve of indomethacin over one dosing interval on Day 1 (P less than 0.01), and at steady state there was a 24% decrease in the maximum plasma concentration (P less than 0.02). The pharmacokinetics of indomethacin were not affected by co-administration of ranitidine. Accumulation of indomethacin after repeated oral dosing was not significantly altered by the co-administration of either misoprostol or ranitidine. The frequency and severity of abdominal symptoms was significantly increased (P less than 0.01) during misoprostol dosing, compared with either ranitidine or placebo plus indomethacin. When the dosing phase (Days 1-8) was compared with the washout phase (Days 9-15) in each period, misoprostol, but not ranitidine or placebo, plus indomethacin resulted in an increase (P less than 0.001) in abdominal symptom severity, frequency of bowel motions and a decrease in faecal consistency.
Kendall
M J
MJ
Department of Medicine, Queen Elizabeth Hospital, Birmingham, UK.
Gibson
R
R
Walt
R P
RP
D015746:Abdominal Pain / Q000139:chemically induced; D000293:Adolescent; D000328:Adult; D003672:Defecation / Q000187:drug effects* / Q000502:physiology; D004064:Digestive System / Q000187:drug effects*; D004347:Drug Interactions; D005243:Feces; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D016595:Misoprostol / Q000009:adverse effects / Q000494:pharmacology*; D011899:Ranitidine / Q000009:adverse effects / Q000494:pharmacology*
D016595:Misoprostol; D011899:Ranitidine; D007213:Indomethacin