Isolated liver with a recirculating perfusate was used to study 3'-azido-3'-deoxythymidine (AZT) disposition in phenobarbitone-pretreated rats at 68 microM AZT concentration in the reservoir. Clearance of AZT in the livers obtained from control animals was 0.42 +/- 0.01 (mean +/- s.d.) mL min-1/10 g liver. Over the study period of 105 min, 12.7 +/- 2.6% of the dose was excreted in bile and of this 95% was recovered as 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine (GAZT). The amount of GAZT found in the perfusate after 105 min of liver perfusion was < 1% of the AZT dose introduced into the reservoir. Phenobarbitone pretreatment of rats resulted in a 5.5-fold increase of AZT clearance. In addition, the area under the perfusate concentration-time curve (AUC0-105 min) for 3'-amino-3'-deoxythymidine (AMT) and for a catabolite of unknown structure was increased 3- and 10-fold, respectively, and the amount of AZT dose excreted in the bile was nearly doubled. Thus phenobarbitone was capable of stimulating both detoxification of AZT to GAZT and bioactivation of AZT to AMT, a catabolite known to be highly toxic to human bone marrow cells. This induction was the result of enhancement of AZT catabolism rather than its transport into the cells, since on incubation of AZT (0-250 microM) with rat isolated hepatocytes, a linear relationship between concentration and amount taken up by the cells was shown. In addition, the rate of AZT uptake was not influenced by KCN, dinitrophenol, or temperature, which is consistent with a simple diffusion of AZT through the hepatocellular membrane.(ABSTRACT TRUNCATED AT 250 WORDS)