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) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial Pco2,Po2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH 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 (AUC0-180), 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 (p < 0.01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (Cmax = 156 +/- 6.5 ng mL-1 against 51 +/- 5.8 ng mL-1 in control; p < 0.05). AUC0-180 was higher (p < 0.05) after omeprazole treatment (18.6 +/- 1.4 micrograms mL-1 min) than in control (6.8 +/- 0.6 microgram 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, being 6.4 +/- 0.1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect- (respiratory depression-) 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 detected. A significant correlation between the area under the effect-time curve (0-120 min) and AUC0-180 has been also observed (r = 0.90; p < 0.01). 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 pH2 solution.
Pharmacology Department, Basque Country University School of Medicine, Leioa, Spain.
J
J
de Castro
C
C
Aguirre
J M
JM
Rodríguez-Sasiaín
E
E
Gómez
M J
MJ
Garrido
R
R
Calvo
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D004347:Drug Interactions; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007408:Intestinal Absorption / Q000187:drug effects; D008691:Methadone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D009853:Omeprazole / Q000008:administration & dosage / Q000494:pharmacology*; D011659:Pulmonary Gas Exchange; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced*; D017693:Sodium Bicarbonate / Q000494:pharmacology
D017693:Sodium Bicarbonate; D009853:Omeprazole; D008691:Methadone