Challenges in exploring the cytochrome P450 system as a source of variation in canine drug pharmacokinetics

Abstract

The cytochrome P450 (CYP) superfamily constitutes a collection of enzymes responsible for the metabolism of a wide array of endo- and xenobiotic compounds. Much of the knowledge on substrate specificity and genetic identification of the various CYP isoforms is derived from research in rodents and humans and only limited information has been captured in the dog. Currently, there exist many gaps in our knowledge of canine CYP diversity as a result of the paucity of studies focusing on canine CYPs, canine CYP polymorphisms, and the therapeutic consequences of these genetic variants. Challenges engendered by this lack of information is further amplified by inter- and intraspecies differences in the specificity and affinity of substrates and inhibitors, prohibiting a simple extrapolation of probe substances used in human CYP research. This creates a need to develop and validate canine-specific CYP probes. Failure to understand this potential metabolic and pharmacogenomic diversity can also influence the interpretation of data generated in dogs to support human drug development. It is with these objectives in mind that we provide an overview of what is currently known about canine CYPs with the hope that it will encourage further exploration into this important area of research.

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

“…It is well-known that midazolam is metabolized to 1'-hydroxymidazolam by CYP3A mainly in humans, mice, rats, dogs, monkeys, pigs [21,39,[58][59][60]. The BA of midazolam in humans was previously reported to be 30.0% [61].…”

“…i.v., intravenous; p.o., peroral; C max , the peak plasma concentration; T max, the time to reach C max ; t 1/2 , terminal elimination half-life; AUC 0-24h, area under the plasma concentration vs. time curve from 0 h to 24 h; V d,ss , volume of distribution; CL tot , total body clearance; BA, bioavailability; N.C., not calculated. paraxanthine because CYP1A2 is the primary enzyme responsible for caffeine metabolism in human, mouse, rat, dog, monkey, and pig livers [37][38][39][40][41][42]. The BA of caffeine in humans was previously reported to be 108% [43].…”

Electrochemistry of Canis familiaris cytochrome P450 2D15 with gold nanoparticles: An alternative to animal testing in drug discovery

“…To this end, a fast and reliable in vitro method would offer the possibility of a more detailed study of the interaction of new drugs with the animal P450 enzymes therefore increasing the predictive value of these preclinical trials. Canis familiaris is one of the most widely studied animal models used in safety determination of new pharmaceuticals [11][12] and, although the major isoforms of the human cytochromes P450 2D6, 3A4, 2E1, 2C19 and 1A2 have been identified in C. familiaris [13][14][15][16], there is still a lack of knowledge on their pharmacogenomic/metabolic diversity [9]. Electrochemical techniques already developed in our lab for human hepatic monooxygenases including cytochromes P450 [17][18][19][20][21][22] represent the ideal approach for a sensitive, accurate and rapid evaluation of animal P450-drug interactions obviating both the requirement for a redox partner and the addition of NADPH cofactor as already reported for some animal P450 enzymes recombinantly expressed in a soluble form [23][24][25].…”

Utility of in vitro clearance in primary hepatocyte model for prediction of in vivo hepatic clearance of psychopharmacons

“…Although plenty of the psychopharmacons included in the present study are known to be metabolized by CYP2D6 (aripiprazole, citalopram, duloxetine, fluoxetine, haloperidol, mianserin, mirtazapine, olanzapine, paroxetine, quetiapine, risperidone, venlafaxine) [26], no correlation of the clearance properties was observed between the dog and the human hepatocytes. It can be explained by the facts 1) that some human CYP2D6 substrates are not metabolized or poorly metabolized by the canine CYP2D15 [24] or 2) that the dog CYP2D15 or the human CYP2D6 are not the exclusive enzymes in the metabolism of most of the drugs.…”

“…This means that in safety studies, the rat is the most relevant laboratory animal to human, since the metabolic properties of the rat is similar to those of human. During drug development, the experimental approaches are generally based on animal models; however, the drug metabolizing systems in the laboratory animals can differ from each other or from human [21][22][23][24]. For example in rabbit, the enzymes of CYP2C subfamily are the most important in drug metabolism, contrary to human where CYP3A enzymes are involved in the metabolism of most of the drugs (approximately 50%) in the market [22,25].…”