Ethanol Interference with Morphine Metabolism in Isolated Guinea Pig Hepatocytes

Abstract

It has previously been shown that guinea pig hepatocytes metabolise morphine in a fashion similar to humans. The metabolism of morphine (5 pM) 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 mathematical model was estimated on experimental data and used to analyse the effects of ehtanol on the reaction rates of the different morphine metabolites. Ethanol inhibited the rate of morphine elimination in a dose-related manner, at the high ethanol concentrations the elimination rate was 40 per cent of the control rate. The formation of morhine-glucuronides was influenced in a biphasic manner. Five and 10 mM ethanol increased both the morphine-3-glucuronide and morphine-6-glucuronide levels after 60 min incubation compared to the control, whereas at the higher ethanol concentrations (25-100 mM) the levels of morphineglucuronides were reduced. Data from the mathematical model, however, demonstrated that the reaction rates for morphine-glucuronide formation were decreased at all ethanol concentrations and in a dose-dependent manner, the interpretation of this-being that at the lower (5 and 10 mM) ethanol concentraions employed in this study, other metabolic pathways of morphine are more heavily inhibited than the glucuronidations, resulting in a shunting towards morphine-3-glucuronide and morphine-6-glucuronide. The pharmacodynamic consequences of these pharmacokinetic effects are thus somewhat diffucult to predict since morphine-6-glucuronide has a higher agonist potency than morphine. At high concentrations ethanol inhibition of morphine metabolism will increase the concentration of morphine and subsequently the euphoric and the toxic effects. The lower quantities of morphine-6-glucuronide formed in the presence of high ethanol concentrations on the other hand most probably imply reduction of such effects and the net pharmacodynamic effect would be uncertain. At low ethanol concentrations, however, morphine-6-glucuronide concentrations increased and morphine metabolism was less inhibited leading to a possible potentiation of the effects of morphine. Thus, a low ehtanol concentration might exert a more pronounced ethanol-drug effect interaction than a higher ethanol concentration.

Differential Inhibition of Morphine Glucuronidation in the 3–and 6–Position by Ranitidine in Isolated Hepatocytes from Guinea Pig*

“…incubation further indicated that the observed effect on morphine metabolism was not mediated through inhibition of unknown pathways. This is in contr;ixf to the observed interaction between morphine and ethaiiol employing the same experimental set up, where part 01' tlic ethanol effect was due to inhibition of some unidentificd pathway (Aasmundstad et a/. 1996).…”

“…The reverse effect was observed whcn administering ethanol. a known cosubstrate (UDPGA) depletor (Bodd et al 1986;Aasmundstad et al 1996). The ratios between inlra-and extra-cellular concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide were not influenced by ranitidine.…”

“…However, apart from ii study on guinea pig liver homogenates demonstrating inhibition of morphine-3-glucuronide and not morphine-6-glucuronide. information is sparsc regarding factors that might influence the niorphinc glucuronidation in either the 3-or 6-direction (Lawrence et d. 1992), Recently, wc rcported that ethanol interacted with morphine metabolism to increase the ratio of morphinc-3-glIicuronide to morphine-6-glucuronide in sus- pensions of isolated guinea pig hepatocytes (Aasmundstad et a/. 1996).…”