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Phytocannabinoid‐rich hemp extracts containing cannabidiol (CBD) and cannabidiolic acid (CBDA) are increasingly being used to treat various disorders in dogs. The objectives of this study were to obtain preliminary information regarding the in vitro metabolism of these compounds and their capacity to inhibit canine cytochrome P450 (CYP)‐mediated drug metabolism and canine P‐glycoprotein‐mediated transport. Pure CBD and CBDA, and hemp extracts enriched for CBD and for CBDA were evaluated. Substrate depletion assays using pooled dog liver microsomes showed CYP cofactor‐dependent depletion of CBD (but not CBDA) and UDP‐glucuronosytransferase cofactor‐dependent depletion of CBDA (but not CBD) indicating major roles for CYP and UDP‐glucuronosytransferase in the metabolism of these phytocannabinoids, respectively. Further studies using recombinant canine CYPs demonstrated substantial CBD depletion by the major hepatic P450 enzymes CYP1A2 and CYP2C21. These results were confirmed by showing increased CBD depletion by liver microsomes from dogs treated with a known CYP1A2 inducer (β‐naphthoflavone) and with a known CYP2C21 inducer (phenobarbital). Cannabinoid‐drug inhibition experiments showed inhibition (IC50 = 4.6–8.1 μM) of tramadol metabolism via CYP2B11‐mediated N‐demethylation (CBD and CBDA) and CYP2D15‐mediated O‐demethylation (CBDA only) by dog liver microsomes. CBD and CBDA did not inhibit CYP3A12‐mediated midazolam 1′‐hydroxylation (IC50 > 10 μM). CBD and CBDA were not substrates or competitive inhibitors of canine P‐glycoprotein. Results for cannabinoid‐enriched hemp extracts were identical to those for pure cannabinoids. These in vitro studies indicate the potential for cannabinoid–drug interactions involving certain CYPs (but not P‐glycoprotein). Confirmatory in vivo studies are warranted. [ABSTRACT FROM AUTHOR]

In 2001 the molecular genetic basis of so‐called "ivermectin sensitivity" in herding breed dogs was determined to be a P‐glycoprotein deficiency caused by a genetic variant of the MDR1 (ABCB1) gene often called "the MDR1 mutation." We have learned a great deal about P‐glycoprotein's role in drug disposition since that discovery, namely that P‐glycoprotein transports many more drugs than just macrocyclic lactones that P‐glycoprotein mediated drug transport is present in more places than just the blood brain barrier, that some cats have a genetic variant of MDR1 that results in P‐glycoprotein deficiency, that P‐glycoprotein dysfunction can occur as a result of drug–drug interactions in any dog or cat, and that the concept of P‐glycoprotein "inhibitors" versus P‐glycoprotein substrates is somewhat arbitrary and artificial. This paper will review these discoveries and discuss how they impact drug selection and dosing in dogs and cats with genetically mediated P‐glycoprotein deficiency or P‐glycoprotein dysfunction resulting from drug–drug interactions. [ABSTRACT FROM AUTHOR]

Orosomucoid polymorphisms influence plasma drug binding in humans; however, canine variants and their effect on drug plasma protein binding have not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1,464 dogs (from 64 breeds and mixed‐breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil, and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n = 12). Free and total drug plasma concentrations were quantified by liquid chromatography–mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n = 1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n = 21). Free drug fractions did not differ significantly (p >.05; Mann‐Whitney U) between plasma collected from dogs with c.70AA (n = 4) and those with c.70GG (n = 8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated. [ABSTRACT FROM AUTHOR]

The ABCB1 gene is responsible for encoding the P-glycoprotein (P-gp) efflux transporter that prevents accumulation of exogenous substances in the body by utilizing ATP hydrolysis to transport these substances against their concentration gradient. In dogs, homozygous or heterozygous mutations for the previously described ABCB1-1Δ mutation lead to ineffective P-gp efflux transport function and puts the animal at risk for potentially devastating adverse drug effects. The purpose of this study was to evaluate ABCB1-1Δ gene mutation status in species belonging to the Canidae family, including each of the following: maned wolf (Chrysocyon brachyurus), gray wolf (Canis lupus), red wolf (Canis rufus), coyote (Canis latrans), dingo (Canis lupus dingo), New Guinea singing dog (Canis lupus dingo), arctic fox (Vulpes lagopus), and fennec fox (Vulpes zerda). These species were chosen based on an evolutionary study conducted by Belyaev that noted foxes, bred for temperament, tended to have similar behaviors seen in the modern-day dog. Wolves, known predecessors to the modern dog, were also included. In the current study, a buccal swab was performed on each animal and then tested at Washington State University's Veterinary Clinical Pharmacology Lab, where they were tested according to previously published methods validating buccal swab samples and polymerase chain reaction (PCR) –based genetic analysis. Knowledge of Canidae species ABCB1-1Δ gene mutation status allows for safe and effective therapeutic treatment of nondomestic animals, ensuring any anticipated adverse drug events are prevented. All eight species were found to have the wild-type ABCB1 gene and thus, expected to have normally functioning P-gp efflux transporters. Although these data can be used to guide clinical decision making, because of a small sample size, a more robust study is necessary to assess Canidae ABCB1-1Δ mutation status comprehensively. [ABSTRACT FROM AUTHOR]