THE EFFECT OF CHANGES IN GASTRIC PH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

The effect of omeprazole (2 mg kg(-1) i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg(-1)) w as examined and compared with control animals that only received metha done. Quantitative assessments of arterial P-CO2, P-O2, PH, and respir atory rate were employed as criteria for evaluation. Intragastric pH w as measured in each rat immediately before and 2 h after methadone. Pl asma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, me asured as the area under the plasma concentration-time curve (AUC(0-18 0)), was also evaluated. The intensity of the methadone-induced respir atory depression was significantly greater in the omeprazole group tha n in control rats. A significant variation (p < 0.01) in all respirato ry parameters was detected from 30 to 120 min after methadone. Omepraz ole caused a significant increase in methadone levels (C-max=156+/-6.5 ng mL(-1) against 51+/-5.8 ng mL(-1) in control; p < 0.05). AUC(0-180 ) was higher (p < 0.05) after omeprazole treatment (18.6+/-1.4 mu g mL (-1) min) than in control (6.8+/-0.6 mu g mL(-1) min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4.7+/-0.1 against 2.2+/-0.04) and continued increasing, bein g 6.4+/-0.1 at the end of the experiment. Correlation was observed bet ween intragastric pH and the area under the effect- (respiratory depre ssion-) time curve (r=0.74; p < 0.001). A relationship between plasma methadone levels at 120 min and gastric PH (r=0.92; p < 0.001) was det ected. A significant correlation between the area under the effect-tim e curve (0-120 min) and AUC(0-180) has been also observed (r=0.90; p < 0.01). These pharmacokinetic and pharmacodynamic changes could be gas tric pH dependent because they were mimicked when gastric pH was exper imentally modified by bicarbonate whereas opposite results were obtain ed with acidic pH 2 solution.