ETHANOL INTERFERENCE WITH MORPHINE-METABOLISM IN ISOLATED GUINEA-PIG HEPATOCYTES

It has previously been shown that guinea pig hepatocytes metabolise mo rphine in a fashion similar to humans. The metabolism of morphine (5 m u M) and the formation of metabolites morphine-3-glucuronide, morphine -6-glucuronide and normorphine was studied in the absence and presence of ethanol (5, 10, 25, 60 and 100 mM) in freshly isolated guinea pig hepatocytes. In order to gain more detailed information, a mathematica l model was estimated on experimental data and used to analyse the eff ects of ehtanol on the reaction rates of the different morphine metabo lites. Ethanol inhibited the rate of morphine elimination in a dose-re lated manner, at the high ethanol concentrations the elimination rate was 40 per cent of the control rate. The formation of morphine-glucuro nides was influenced in a biphasic manner. Five and 10 mM ethanol incr eased both the morphine-3-glucuronide and morphine-6-glucuronide level s after 60 min incubation compared to the control, whereas at the high er ethanol concentrations (25-100 mM) the levels of morphine-glucuroni des were reduced. Data from the mathematical model, however, demonstra ted that the reaction rates for morphine-glucuronide formation were de creased at all ethanol concentrations and in a dose-dependent manner, the interpretation of this being that at the lower (5 and 10 mM) ethan ol concentraions employed in this study, other metabolic pathways of m orphine are more heavily inhibited than the glucuronidations, resultin g in a shunting towards morphine-3-glucuronide and morphine-6-glucuron ide. The pharmacodynamic consequences of these pharmacokinetic effects are thus somewhat diffucult to predict since morphine-6-glucuronide h as a higher agonist potency than morphine. At high concentrations etha nol inhibition of morphine metabolism will increase the concentration of morphine and subsequently the euphoric and the toxic effects. The l ower quantities of morphine-6-glucuronide formed in the presence of hi gh ethanol concentrations on the other hand most probably imply reduct ion of such effects and the net pharmacodynamic effect would be uncert ain. Al low ethanol concentrations, however, morphine-6-glucuronide co ncentrations increased and morphine metabolism mas less inhibited lead ing to a possible potentiation of the effects of morphine. Thus, a low ehtanol concentration might exert a more pronounced ethanol-drug effe ct interaction than a higher ethanol concentration.