Development and application of a physiologically based pharmacokinetic model for ethanol in the mouse.
The purpose of the present study was to develop a physiologically based pharmacokinetic (PBPK) model in the mouse and to utilize it to evaluate the relative contribution, if any, of gastric alcohol dehydrogenase (ADH) to the bioavailability of ethanol. The PBPK model developed in Swiss Webster male mice accurately simulated blood and brain ethanol concentrations following an intraperitoneal administration of 0.82 and 3.2 g of ethanol/kg body weight. Application of the model illustrated that inclusion of gastric ADH into the model provided a less accurate fit to the experimental data, and therefore gastric ADH did not contribute to the overall disposition of an orally administered ethanol dose of 0.75 g/kg. Furthermore, the model also indicated that changes in percentage cardiac output to the liver had a minimal effect on the blood ethanol concentration (BEC) time curve. The results illustrate the validity of the PBPK model developed for ethanol and demonstrate that in the Swiss Webster male mouse the bioavailability of ethanol is minimally affected, if at all, by metabolism by gastric ADH.
Pastino
G M
GM
UMDNJ New Jersey Medical School, Department of Pharmacology and Toxicology, Newark 07103, USA.
Sultatos
L G
LG
Flynn
E J
EJ
D000426:Alcohol Dehydrogenase / Q000502:physiology; D000435:Alcoholic Intoxication / Q000503:physiopathology*; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000493:pharmacokinetics*; D005753:Gastric Mucosa / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D051379:Mice
D000431:Ethanol; D000426:Alcohol Dehydrogenase