Short-term metabolic ethanol tolerance in dogs.

Metabolic ethanol tolerance was studied in a cohort of five dogs with ethanol challenge repeated weekly over a 7-week period. During the 7-week period, the area under the blood alcohol versus time curve (AUC) increased slightly while the rate of ethanol elimination also increased slightly. During the repeated ethanol dosing, ethanol absorption shifted from approximately equal absorption in the stomach and intestine to three-fold more absorption in the intestine than in the stomach. The likely cause of the shift in absorption site was probably a concomitant change in gastric emptying that occurred with repeated dosing. This shift is significant since ethanol absorption in the small intestine has been shown to be over six-fold more rapid than ethanol absorption in the stomach.

Monte Carlo simulation of an ethanol pharmacokinetic model.

BACKGROUND: One challenge of using even relatively simple pharmacokinetic models is valuation of model parameters. Unknown model parameter values can be determined by fitting the model to measured data. Goals of the present study were to (1) obtain ethanol pharmacokinetic data from a cohort of dogs, (2) propose a physiologic ethanol pharmacokinetic model, (3) and perform Monte Carlo simulation to determine model parameter values. The rationale for the particular model proposed here was to account for the interrelationship between blood ethanol concentration and gastrointestinal physiology. METHODS: To each of five fasted dogs, 1 g of ethanol/kg body weight was administered as a gavage of 20% w/v ethanol solution. Developed was an ethanol pharmacokinetic model that comprised a gastric emptying mechanism, a body water compartment, ethanol diffusion through the stomach mucosa, gastric alcohol dehydrogenase (GADH) oxidation of ethanol, diffusion through the small intestine epithelia to the villi, a countercurrent exchanger model of the villi, and liver alcohol dehydrogenase oxidation of ethanol. Monte Carlo simulation was used to estimate model parameter values and standard deviations by minimization of the chi function. RESULTS: Fitting the experimental data to the model using Monte Carlo simulation yielded reasonable values for model parameters. The model predicted that the capacity for ethanol absorption in the intestine was 6.79-fold greater than the ethanol absorption capacity in the stomach. The model indicated that 23.8 +/- 8.3% of the ethanol dose was actually absorbed in the stomach, and an insignificant amount of ethanol was metabolized by GADH. CONCLUSIONS: Ethanol metabolism by GADH is insignificant in the present case. The blood ethanol profile was strongly determined by gastric emptying. Differences between experimental data and simulation results largely result from the gastric emptying model selected. Therefore, accuracy of the complete pharmacokinetic model can be improved significantly by improving the gastric emptying model.

Effects of food on ethanol metabolism.

The goals of the present study were (1) to obtain ethanol pharmacokinetic data from fed dogs, and (2) perform Monte Carlo simulation to determine the effect of food on pharmacokinetic model parameter values. To a cohort of five fed dogs, 1 g ethanol per km body weight was administered as a gavage of 20% w/v ethanol solution. Blood samples taken at 0, 10, 20, 30, 40, 60, 80, 100, 120, 180, 240, and 360 minutes after the dose were mixed with anticoagulant and stored on ice. Blood ethanol concentration was determined via headspace chromatograph. Monte Carlo simulation with an ethanol pharmacokinetic model was used to estimate model parameter values and parameter standard deviations by minimization of the chi-squared function. Results indicate that 50.6 +/- 21.0% of the ethanol dose was absorbed in the stomach, and an insignificant amount of ethanol was metabolized by gastric alcohol dehydrogenase postulated for the model. At 6 hours after the ethanol dose 59.4 +/- 21.0% of the ethanol dose was retained in the dogs' stomachs.