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

Abstract

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).

Drug-drug interactions in ageing HIV-infected individuals

“…The physicochemical properties of some drugs can alter gastrointestinal pH and influence the ionization, disintegration and dissolution of co-administered drugs (de Castro et al, 1996;Yang et al, 2012). Such instance can lead to erratic absorption behaviour of pH-sensitive drugs like furosemide and triazolam.…”

Drug-drug interactions in ageing HIV-infected individuals

“…The physicochemical properties of some drugs can alter gastrointestinal pH and influence the ionization, disintegration and dissolution of co-administered drugs (de Castro et al, 1996;Yang et al, 2012). Such instance can lead to erratic absorption behaviour of pH-sensitive drugs like furosemide and triazolam.…”

Actual and Potential Drug Interactions Associated with Methadone

“…de Castro et al. [134] found that methadone‐induced respiratory depression was more pronounced in rats administered omeprazole as compared with placebo. Omeprazole pretreatment produced a marked and significant increase in the respiratory depressant effect of methadone.…”

“…These results confirm that pH, not P450 involvement, was the mechanism behind the changes seen with the omeprazole group. As this was a single‐dose study, it is therefore unlikely that P450 enzymes played a role in the results found [134]. The authors suggest that although the majority of methadone is absorbed in the small intestine, small changes or interindividual differences in gastric pH may influence plasma methadone concentrations [134].…”

Methadone

“…Oral absorption is affected by gut motility, pH of gastric mucosa, gut perfusion, and pharmacokinetic properties of the drug. 5 Oral bioavailability is between 70% and 80% but ranges from 36% to 100%. This is probably due to the variable activity of the cytochrome P450-3A4 system that is responsible for the metabolism of methadone.…”

Drug-drug interactions in ageing HIV-infected individuals

“…The physicochemical properties of some drugs can alter gastrointestinal pH and influence the ionization, disintegration and dissolution of co-administered drugs (de Castro et al, 1996;Yang et al, 2012). Such instance can lead to erratic absorption behaviour of pH-sensitive drugs like furosemide and triazolam.…”

Actual and Potential Drug Interactions Associated with Methadone

“…de Castro et al. [134] found that methadone‐induced respiratory depression was more pronounced in rats administered omeprazole as compared with placebo. Omeprazole pretreatment produced a marked and significant increase in the respiratory depressant effect of methadone.…”

“…These results confirm that pH, not P450 involvement, was the mechanism behind the changes seen with the omeprazole group. As this was a single‐dose study, it is therefore unlikely that P450 enzymes played a role in the results found [134]. The authors suggest that although the majority of methadone is absorbed in the small intestine, small changes or interindividual differences in gastric pH may influence plasma methadone concentrations [134].…”

Methadone

“…Oral absorption is affected by gut motility, pH of gastric mucosa, gut perfusion, and pharmacokinetic properties of the drug. 5 Oral bioavailability is between 70% and 80% but ranges from 36% to 100%. This is probably due to the variable activity of the cytochrome P450-3A4 system that is responsible for the metabolism of methadone.…”

Drug-drug interactions in ageing HIV-infected individuals

“…The physicochemical properties of some drugs can alter gastrointestinal pH and influence the ionization, disintegration and dissolution of co-administered drugs (de Castro et al, 1996;Yang et al, 2012). Such instance can lead to erratic absorption behaviour of pH-sensitive drugs like furosemide and triazolam.…”

Actual and Potential Drug Interactions Associated with Methadone

“…de Castro et al. [134] found that methadone‐induced respiratory depression was more pronounced in rats administered omeprazole as compared with placebo. Omeprazole pretreatment produced a marked and significant increase in the respiratory depressant effect of methadone.…”

“…These results confirm that pH, not P450 involvement, was the mechanism behind the changes seen with the omeprazole group. As this was a single‐dose study, it is therefore unlikely that P450 enzymes played a role in the results found [134]. The authors suggest that although the majority of methadone is absorbed in the small intestine, small changes or interindividual differences in gastric pH may influence plasma methadone concentrations [134].…”

Methadone

“…Oral absorption is affected by gut motility, pH of gastric mucosa, gut perfusion, and pharmacokinetic properties of the drug. 5 Oral bioavailability is between 70% and 80% but ranges from 36% to 100%. This is probably due to the variable activity of the cytochrome P450-3A4 system that is responsible for the metabolism of methadone.…”