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.
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.
Pastino
G M
GM
Schering Plough Research Institute, Lafayette, New Jersey 07848, USA. gina.pastino@spcorp.com
Conolly
R B
RB
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005753:Gastric Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D051381:Rats
D000431:Ethanol