title: Canine CYP2B11 metabolizes and is inhibited by anesthetic agents often co-administered in dogs.
abstract: Medetomidine is a well-established sedative and analgesic for dogs and cats. As a premedicant for anesthesia regimens that also include other agents, medetomidine can also provide a dose-sparing effect. While there are likely several reasons for the dose-sparing effect of medetomidine, the role of metabolic drug-drug interactions at the single enzyme level has not yet been examined. Using a panel of individually expressed canine cytochromes P450 cloned from beagle liver, this report demonstrates that medetomidine is an extremely potent CYP2B11 inhibitor (IC(50) < 10 nm) and that ketamine and midazolam are CYP2B11 substrates with high intrinsic clearances. These in vitro findings suggest that under some circumstances, medetomidine (i.e. 'perpetrator') may inhibit the metabolic clearance of some high metabolic clearance drugs (i.e. 'victims') with which it is commonly co-administered via the CYP2B11 pathway. However, as the dose-sparing effect of medetomidine premedication commonly results in anesthetic dose reduction, any increased plasma concentrations of victim drugs caused by medetomidine would still be lower than if no dose reduction had been made. Further studies are needed to characterize whether medetomidine possesses the potential to cause pharmacokinetic interactions. In conclusion, the ability of recombinant P450s to define canine-specific drug clearance pathways and P450 inhibitors should prove useful in identifying drug combinations that may require dose adjustments in dogs.
authors.affiliation: Pfizer Global Research and Development, Pharmacokinetics, Dynamics, and Metabolism, Creve Coeur, MO, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Baratta
authors.forename: M J
authors.initials: MJ
authors.lastname: Zaya
authors.forename: J A
authors.initials: JA
authors.lastname: White
authors.forename: C W
authors.initials: CW
authors.lastname: Locuson
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003001:Cloning, Molecular; D000072467:Cytochrome P450 Family 2; D004285:Dogs / Q000378:metabolism*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000777:Anesthetics; D006993:Hypnotics and Sedatives; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D000072467:Cytochrome P450 Family 2; C090278:cytochrome P-450 CYP2B11 (dog)