Alcohol ADME in Primates Studied with Positron Emission Tomography
ABSTRACT The sensitivity to the intoxicating effects of alcohol as well as its adverse medical consequences differ markedly among individuals, which reflects in part differences in alcohol's absorption, distribution, metabolism, and elimination (ADME) properties. The ADME of alcohol in the body and its relationship with alcohol's brain bioavailability, however, is not well understood.
The ADME of C-11 labeled alcohol, CH(3) (11)CH(2)OH, 1 and C-11 and deuterium dual labeled alcohol, CH(3) (11)CD(2)OH, 2 in baboons was compared based on the principle that C-D bond is stronger than C-H bond, thus the reaction is slower if C-D bond breaking occurs in a rate-determining metabolic step. The following ADME parameters in peripheral organs and brain were derived from time activity curve (TAC) of positron emission tomography (PET) scans: peak uptake (C(max)); peak uptake time (T(max)), half-life of peak uptake (T(1/2)), the area under the curve (AUC(60min)), and the residue uptake (C(60min)).
For 1 the highest uptake occurred in the kidney whereas for 2 it occurred in the liver. A deuterium isotope effect was observed in the kidneys in both animals studied and in the liver of one animal but not the other. The highest uptake for 1 and 2 in the brain was in striatum and cerebellum but 2 had higher uptake than 1 in all brain regions most evidently in thalamus and cingulate. Alcohol's brain uptake was significantly higher when given intravenously than when given orally and also when the animal was pretreated with a pharmacological dose of alcohol.
The study shows that alcohol metabolism in peripheral organs had a large effect on alcohol's brain bioavailability. This study sets the stage for clinical investigation on how genetics, gender and alcohol abuse affect alcohol's ADME and its relationship to intoxication and medical consequences.
Full-textDOI: · Available from: Youwen Xu, May 28, 2015
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ABSTRACT: Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we measured the effect of alcohol on metabolism of [3-(13) C]pyruvate in the adult Guinea pig brain cortical tissue slice and compared the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2-(13) C]ethanol. Analyses of metabolic profile clusters suggests that the significant reductions in metabolism induced by ethanol (10, 30 and 60 mM) are via action at neurotransmitter receptors, particularly α4β3δ receptors, while very low concentrations of ethanol may produce metabolic responses due to release of GABA via GAT1 and the subsequent interaction of this GABA with local α5- or α1-containing GABA(A)R. There was no measureable metabolism of [1,2-(13) C]ethanol with no significant incorporation of (13) C from [1,2-(13) C]ethanol into any measured metabolite above natural abundance, although there were measurable effects on total metabolite sizes similar to those seen with unlabeled ethanol. This article is protected by copyright. All rights reserved.Journal of Neurochemistry 04/2014; 129:304-314.. DOI:10.1111/jnc.12634 · 4.24 Impact Factor