The influence of anesthetic agents on rat hepatic cytochromes P450 in vivo.
The objective of this study was to identify which anesthetics when used acutely will affect cytochrome P450 (CYP) activity in male Sprague-Dawley rats in vivo. The anesthetics tested were fentanyl citrate, alpha-chloralose, ketamine, urethane (ethyl carbamate), halothane, and ether. CO2 anesthesia was used as the control comparator. Theophylline was used as a probe for CYP1A activity, phenobarbital for CYP2B/2C, flecainide for CYP2D1, and ethosuximide for CYP3A activity. All probes were administered via tail vein injection after anesthetic-induced loss of the righting reflex. Single sample probe clearances were estimated, and used as an index of CYP activity. Fentanyl citrate, alpha-chloralose, halothane, and ether did not have statistically significant effects on any of the CYP activities. Ketamine did not significantly affect CYP1 or CYP2B/2C activity. However, it decreased the clearance of flecainide (i.e. CYP2D1 activity) by 13.4% (p < 0.001) and the clearance of ethosuximide (i.e. CYP3A activity) by 17.6% (p < 0.0001). Urethane increased the clearance of theophylline by 91.5% (p < 0.0001), and decreased the clearance of ethosuximide by 40.5% (p < 0.0001) though it did not affect CYP2B/2C or CYP2D1 activities significantly. From this data, we conclude that a single dose of ketamine mildly inhibits the activity of CYP2D1 and CYP3A, and a single dose of urethane strongly inhibits CYP3A but increases CYP1A activity.
Loch
J M
JM
University of Toledo College of Pharmacy, Department of Pharmacology, Ohio 43606, USA.
Potter
J
J
Bachmann
K A
KA
D000704:Analysis of Variance; D018681:Anesthetics, General / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D002698:Chloralose / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D004986:Ether / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014520:Urethane / Q000494:pharmacology
D018681:Anesthetics, General; D004986:Ether; D002698:Chloralose; D014520:Urethane; D007649:Ketamine; D003577:Cytochrome P-450 Enzyme System; D005283:Fentanyl; D006221:Halothane