EFFECTS OF CHRONIC INGESTION OF ETHANOL ON THE DISTRIBUTION PHARMACOKINETIC PARAMETERS OF MODEL DRUGS IN RATS.

摘要

The blood level pharmacokinetics of sulfanilamide (SN) and sulfisoxazole (SX) were studied in the moderately ethanol-treated rats (4g/kg/day ethanol for 28 days) and those of procainamide (PA) were studied in both the moderately-ethanol-treated rats and the mixed-ethanol-treated rats (4g/kg/day ethanol for 7 days and 8g/kg/day ethanol for subsequent 21 days). The two-compartment pharmacokinetic analysis of the data indicated that, while the chronic ethanol treatment had no effect on the pharmacokinetics of SN and SX, the chronic ethanol treatments significantly affected certain distribution pharmacokinetic parameters of PA in the body. It was noted that, the central compartment distribution volume (V(,c)) of PA was higher and its rate constant of transport from the central compartment to the tissue compartment (k(,12)) and the initial rate of change of volume of distribution (RVd(,0)) were lower, in the treated rats than those in the control rats. These effects on the distribution characteristics of positively charged PA observed, with no effect on its body clearance, metabolism or steady-state volume of distribution, were explained on the basis of the known effects of chronic ethanol treatment on the structure and composition of tissue cell membranes. The proposed mechanism also explained the lack of effects of the chronic ethanol treatment on the distribution of negatively charged SX and neutral SN.;The effects of the mixed-ethanol treatment on the partition coefficients (R(,T)) of PA in various tissues of rats were studied. The significantly lower R(,T) values noted in the heart and kidneys of the treated rats were attributed to the decreased binding of PA to these tissues and the significantly higher R(,T) value noted in the fat of the treated rats was attributed to the possible decrease in the lipid content of the adipocytes.;The tissue level pharmacokinetics of PA showed that its disappearance rate constants ((beta)) in the heart, skeletal muscles and fat of the mixed-ethanol treated rats were significantly greater than those of the control rats. The mechanisms responsible for this effect were attributed to the different biochemical effects of chronic ethanol treatment on these tissues.