Respiratory effects of diazepam/methadone combination in rats: A study based on concentration/effect relationships

摘要: a b s t r c Background: Methadone may cause respiratory depression and fatalities. Concomitant use of benzodi- azepines in methadone-treated patients for chronic pain or as maintenance therapy opiate abuse is common. However, the exact contribution benzodiazepines to methadone-induced toxicity remains debatable. Methods: We investigated effects combination diazepam (20 mg/kg)/methadone (5 mg/kg) rat, focusing on methadone concentration/effect relationships. Respiratory were studied using arterial blood gases whole-body plethysmography. Plasma concentrations both R- S-methadone enantiomers measured high-performance liquid chiral chromatography coupled mass spectrometry. To clarify mechanisms diazepam/methadone interaction, metabolism was vitro rat liver microsomes. Results: Diazepam/methadone co-administration significantly increased methadone-related inspiratory time (p < 0.001) but did not alter other parameters when compared with alone, despite significant increase area under curve plasma R-methadone during 240 min 0.05). co-incubation microsomes resulted inhibition 0.01), 50%-inhibitory 25.02 ± 0.18 mol/L 25.18 0.23 S- methadone, respectively. Conclusion: concluded that high-doses rats responsible additional comparison metabolic interaction between drugs. In humans, although our experimental data suggest relative safety benzodiazepine/methadone co-prescription, physicians should remain cautious underlying conditions enhance this drug-drug interaction.