Several studies have shown that halothane may influence drug disposition in animals and humans, but the mechanism remains unclear. The relative contributions of changes in metabolizing capacity and hepatic blood flow to altered drug disposition were investigated during halothane anesthesia, using propranolol as a model compound. The studies were performed on six dogs on three separate days; first, the day before anesthesia, second, during halothane (2.0 MAC) anesthesia, and third, 24 h after anesthesia. Each dog simultaneously received 40 mg unlabeled propranolol directly into the portal vein and 200 mCi of3H-propranolol intravenously via chronically implanted catheters. Blood samples were taken every 5 min for the first hour and then every 15 min for a further 3 h for the measurement of unlabeled and3H-propranolol concentrations. During halothane anesthesia, intra-portal–intrinsic clearance was decreased by 62% (P< 0.05) from 2,110 ± 298 to 799 ± 233 ml/min, while systemic clearance was decreased (P< 0.05) from 470 ± 33 ml/min preanesthesia to 280 ± 38 ml/min during halothane anesthesia. The intravenous elimination half-life was increased (P< 0.05) from 87 ± 12 to 155 ± 23 min during anesthesia. Although halothane anesthesia tended to lower liver plasma flow from 642 ± 80 to 473 ± 47 ml/min, this change was not significant. The large change in portal or intrinsic clearance indicates that halothane anesthesia markedly inhibits drug-metabolizing ability. The authors therefore conclude that the alterations in drug disposition observed during halothane anesthesia are mainly due to inhibition of drug-metabolizing capacity in the liver.