The effect of omeprazole (2 mg kg-' i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg-I) was examined and compared with control animals that only received methadone.
Quantitative assessments of arterial pco2, po,, pH, and respiratory rate were employed as criteria for evaluation. Intragastric p H was measured in each rat immediately before and 2 h after methadone.
Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration-time curve (AUC,,,, ), was also evaluated.
The intensity of the methadone-induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation ( j < O . O 1 ) in all respiratory parameters was detected from 30 to 120 min after methadone.
Omeprazole caused a significant increase in methadone levels (C,,,,, = 156f 6.5ngmL-' against 51 f5.8ngmL-' in control; p<0.05). AUC,,,, was higher 0, < 0.05) after omeprazole treatment ( I 8.6f 1.4 pg mL-l min) than in control (6.8 f 0.6 pg mL-min).
Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4.7 f 0.1 against 2.2 f0.04) and continued increasing, being 6.4 f 0.1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect-(respiratory depression-) time curve (Y = 0.74; p<O.OOl). A relationship between plasma methadone levels at 120min and gastric p H (r = 0.92; p i 0.001) was detected. A significant correlation between the area under the effect-time curve (0-120 min) and AUC,,,, has been also observed (r = 0.90; These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH 2 solution.
p<O.Ol).