Application of a Physiologically Based Pharmacokinetic Model to Estimate the Bioavailability of Ethanol in Male Rats: Distinction between Gastric and Hepatic Pathways of Metabolic Clearance

Abstract

A portion of ingested ethanol does not reach the systemic circulation in both rats and humans as indicated by higher blood ethanol concentrations following an intravenous administration compared to an equivalent oral administration. The mechanism for this decrease in the oral bioavailability is not yet completely understood. Metabolism by gastric or hepatic alcohol dehydrogenase (ADH), or both, has been implicated. However, the extent to which each pathway of elimination contributes to the first-pass clearance is not known. The purpose of this study was to utilize a physiologically based pharmacokinetic (PBPK) model for ethanol to estimate the relative contributions of hepatic and gastric metabolic clearance to the oral bioavailability of ethanol in male rats. In the current model, calculations of hepatic-first pass metabolic clearance accounted for the competition for metabolism between incoming ethanol from the GI tract and recirculating ethanol. This differs from previous methods that quantified the effect of ethanol entering the liver from the GI tract on the overall rate of metabolism of ethanol by the liver. These models did not specifically describe the effect of recirculating ethanol on the first-pass metabolism of ethanol, and vice versa. The dependence of bioavailability on dose and absorption rate was also investigated. The use of a PBPK model for ethanol in rats allows a more detailed examination of physiological and biochemical factors affecting the bioavailability of ethanol than has previously been possible. The analysis indicates that both gastric and hepatic first-pass metabolism of ethanol contribute to ethanol bioavailability in male rats.

Specific Alterations of Extracellular Endocannabinoid Levels in the Nucleus Accumbens by Ethanol, Heroin, and Cocaine Self-Administration

“…1a). The rise and fall of 2-AG levels followed a temporal pattern similar to the profile of blood alcohol concentrations after oral administration (Pastino and Conolly, 2000). The relative change in dialysate 2-AG levels was positively correlated with the amount of ethanol consumed ( Fig.…”

Mechanisms of Reversible GABAAReceptor Plasticity after Ethanol Intoxication

“…High peak [EtOH] was observed within 2 min of the 3 g/kg dose (Fig. 8 A) because intraperitoneal injection bypasses the initial gastric and hepatic metabolism by alcohol dehydrogenase (Pastino and Conolly, 2000). In contrast, peak [EtOH] of ϳ60 mM was reached only by 1 h after gavage administration thereafter declining at the same rate as the 3 g/kg intraperitoneal dose.…”

"Infusão de glicose e tiamina em ratos tratados com dose aguda de etanol"

“…Ocorre no estômago, portanto, um efeito de primeira passagem do etanol (Pastino e Conolly, 2000;Parlesak, Billinger et al, 2004).…”

“…A via da álcool desidrogenase confere uma cinética de eliminação do etanol de ordem zero, ou seja, há uma relação de dose-dependência na qual, em alta concentração, o sistema torna-se saturado (Winek e Murphy, 1984;Pastino e Conolly, 2000;Fujimiya, Ohbora et al, 2003).…”

“…Os métodos utilizados podem ser químicos, colorimétricos, enzimáticos ou cromatográficos, sendo este último o padrão de excelência. (Yost, 2002) e somente uma pequena fração é absorvida pelo estômago (Levitt, Li et al, 1997), sendo que nos dois órgãos a absorção é dependente do esvaziamento gástrico (Jones, Jonsson et al, 1997;Oneta, Simanowski et al, 1998;Pastino e Conolly, 2000;Klockhoff, Naslund et al, 2002).…”