PHARMACOKINETIC STUDIES USING MICRODIALYSIS PROBES IN SUBCUTANEOUS TISSUE - EFFECTS OF THE COADMINISTRATION OF ETHANOL AND ACETAMINOPHEN

Loop geometry microdialysis probes with membrane lengths of 40-60 mm were used to monitor the effects of acute and chronic doses of ethanol on acetaminophen pharmacokinetics in awake, freely-moving rats. Microdialysis probes used in this configuration provide very high concentration recoveries and good precision at flow rates below 2 mul min-1. The ability of microdialysis to monitor pharmacokinetics in subcutaneous tissue and blood vessels is compared. Dialysates acquired simultaneously from both blood vessels and subcutaneous tissue showed corresponding disposition for acetaminophen. Acute intraperitoneal doses of ethanol (1 ml kg-1) are shown to increase the relative bioavailability, measured as AUC, by 40%, elimination half-life by 24%. and changes in CL and V(d) were also observed. Larger doses of ethanol, up to 2 ml kg-1, had a similar incremental effect on the pharmacokinetic parameters in some animals, but apparent decreased abdominal blood flow in others caused diminished absorption and drastically altered pharmacokinetic parameters. Chronic doses of ethanol (5% in drinking water for 14 days) caused an increase in bioavailability and other pharmacokinetic parameters, but changes were not as significant as following acute doses. Acute doses of ethanol (1 ml kg-1) were also observed to change the pharmacokinetics of acetaminophen at hepatotoxic levels of the drug. However, acute intraperitoneal doses of acetaminophen (10 mg kg-1) were observed not to have an effect on ethanol pharmacokinetics.