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 bolus and a continuous injection study in rabbits receiving artificial ventilation. In a bolus injection study, the inhalation of 1.0% HAL significantly increased the half-life and the area under the curve and decreased the clearance of CZZ compared with those variables in midazolam administration. In a continuous injection study, the effect of various concentrations of inhaled HAL on plasma CZZ concentration at steady state was compared. Systolic and diastolic arterial blood pressure were decreased dose-dependently after 0.5%, 1.0%, or 2.0% HAL was inhaled. Although the plasma concentration of CZZ was increased 2.5-fold after 3 h of HAL inhalation, there was no significant difference in mean plasma concentrations among the groups treated with 0.5%, 1.0%, or 2.0% HAL. In contrast, the plasma concentration of lidocaine, a substrate for CYP3A, remained unchanged after 1.0% HAL was inhaled. These results suggest that general anesthesia obtained with HAL inhalation will affect the metabolism of drugs administered concomitantly when the drug is a substrate for CYP2E1.
Tateishi
T
T
Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Watanabe
M
M
Nakura
H
H
Tanaka
M
M
Kumai
T
T
Aoki
T
T
Kobayashi
S
S
D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002753:Chlorzoxazone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D006221:Halothane / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits
D018685:Anesthetics, Inhalation; D000779:Anesthetics, Local; D009125:Muscle Relaxants, Central; D008012:Lidocaine; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone; D006221:Halothane