EFFECT OF OMEPRAZOLE ON CONCENTRATIONS OF CLARITHROMYCIN IN PLASMA AND GASTRIC TISSUE AT STEADY-STATE

This study was conducted to determine (i) the effect of omeprazole on steady-state concentrations of clarithromycin and 14-(R)-hydroxyclarit hromycin in plasma and gastric mucosa, (ii) the effect of clarithromyc in on steady-state concentrations of omeprazole in plasma, and (iii) t he effect of clarithromycin on the suppression of gastric acid secreti on by omeprazole. Twenty healthy, Helicobacter pylori-negative male su bjects completed this three-period, double-blind, randomized crossover study. In period 1, all subjects received 40 mg of omeprazole each mo rning for 6 days. Twenty-four-hour gastric pH monitoring took place on days -1 and 6. Pharmacokinetic sampling took place on day 6. In perio ds 2 and 3, subjects were randomly assigned to receive either 40 mg of omeprazole or omeprazole placebo daily for 6 days plus clarithromycin (500 mg) every 8 h for 5 days with a single 500-mg dose on day 6. Gas tric tissue and mucus samples were obtained via endoscopy on day 5. Ga stric pH monitoring and pharmacokinetic sampling took place on day 6. Two week washout intervals separated the three study periods. Clarithr omycin increased mean omeprazole area under the concentration-time cur ve from 0 to 24 h from 3.3 +/- 2.0 to 6.3 +/- 4.5 mu g . h/ml (P < 0.0 5) and harmonic mean half-life from 1.2 to 1.6 h (P < 0.05) but did no t significantly alter the effect of omeprazole on gastric pH. Mean cla rithromycin area under the concentration-time curve from 0 to 8 h incr eased from 22.9 +/- 5.5 (placebo) to 26.4 +/- 5.7 mu g . h/ml (omepraz ole) (P < 0.05) when clarithromycin was administered with omeprazole. Analysis of variance revealed that mean concentrations of clarithromyc in in tissue and mucus were statistically significantly higher when cl arithromycin was given with omeprazole than when clarithromycin was gi ven with placebo (P < 0.001). Mean maximum observed concentrations of clarithromycin in the gastric fundus increased from 20.8 +/- 7.6 (plac ebo) to 24.3 +/- 6.4 mu g/g (omeprazole), and those in the gastric muc us increased from 4.2 +/- 7.7 (placebo) to 39.3 +/- 32.8 mu g/g (omepr azole), Similar increases were observed for the 14-(R)-hydroxyclarithr omycin. These results show that omeprazole increases concentrations of clarithromycin in gastric tissue and mucus and may provide a mechanis m for synergy between clarithromycin and omeprazole that explains the excellent eradication of H. pylori seen in clinical trials.