Ta. Aasmundstad et al., ETHANOL INTERFERENCE WITH MORPHINE-METABOLISM IN ISOLATED GUINEA-PIG HEPATOCYTES, Pharmacology & toxicology, 79(3), 1996, pp. 114-119
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.