USE OF A 2-COMPARTMENT MODEL TO ASSESS THE PHARMACOKINETICS OF HUMAN ETHANOL-METABOLISM

The relationship between blood ethanol concentration and hepatic ethan ol metabolism commonly is calculated using the Michaelis-Menten equati on and a one-compartment model that assumes equality of blood and hepa tic ethanol concentrations. However, at low blood concentrations, most of the ethanol arriving at the liver is metabolized, and hepatic etha nol concentrations may fall far below that of the entering blood. We h ave developed a two-compartment model of ethanol metabolism that accou nts for the fall in ethanol concentration that may occur as blood trav erses the liver and used this model to make predictions concerning eth anol metabolism at various blood ethanol concentrations. The two-compa rtment model predicts that near-complete saturation will occur more ab ruptly and at a lower blood concentration (similar to 3 mM) than is th e case with the one-compartment model. Thus, the two-compartment model predicts a near-constant ethanol elimination rate for blood ethanol c oncentrations above 3 mM (as commonly observed in human subjects), whe reas the one-compartment model predicts an increasing elimination rate over the range of concentrations observed in experimental studies. In agreement with observed data, the two-compartment model predicts that first-pass metabolism should be extremely sensitive to the rate of et hanol absorption. Application of this model to previously published da ta indicated that, when absorption was slowed via concomitant food ing estion, first-pass metabolism accounts far similar to 50% end 10% of e thanol dosages of 0.15 g/kg and 0.3 g/kg, respectively. When ingested without food, there is negligible first-pass metabolism of even very s mall ethanol dosages (0.15 g/kg), These findings suggest that first-pa ss metabolism is an unimportant determinant of the blood ethanol respo nse to ingestion of potentially inebriating doses of ethanol.