HALOTHANE INHALATION INHIBITS THE METABOLISM OF CHLORZOXAZONE, A SUBSTRATE FOR CYP2E1, IN RABBITS

We demonstrated the inhibitory effect of halothane (HAL) inhalation on the metabolism of chlorzoxazone (CZZ), a substrate for CYP2E1, in a b olus and a continuous injection study in rabbits receiving artificial ventilation. In a bolus injection study, the inhalation of 1.0% HAL si gnificantly increased the half-life and the area under the curve and d ecreased the clearance of CZZ compared with those variables in midazol am administration. In a continuous injection study, the eff eet of var ious concentrations of inhaled HAL on plasma CZZ concentration at stea dy state was compared. Systolic and diastolic arterial blood pressure were decreased dose-dependently after 0.5%, 1.0%, or 2.0% HAL was inha led. Although the plasma concentration of CZZ was increased 2.5-fold a fter 3 h of HAL inhalation, there was no significant difference in mea n plasma concentrations among the groups treated with 0.5%, 1.0%, or 2 .0% HAL. In contrast, the plasma concentration of lidocaine, a substra te for CYP3A, remained unchanged after 1.0% HAL was inhaled. These res ults suggest that general anesthesia obtained with HAL inhalation will affect the metabolism of drugs administered concomitantly when the dr ug is a substrate for CYP2E1.