Translating Pharmacogenetics and Pharmacogenomics to the Clinic: Progress in Human and Veterinary Medicine

Abstract

As targeted personalized therapy becomes more widely used in human medicine, clients will expect the veterinary clinician to be able to implement an evidence-based strategy regarding both the prescribing of medicines and also recognition of the potential for adverse drug reactions (ADR) for their pet, at breed and individual level. This review aims to provide an overview of current developments and challenges in pharmacogenetics in medicine for a veterinary audience and to map these to developments in veterinary pharmacogenetics. Pharmacogenetics has been in development over the past 100 years but has been revolutionized following the publication of the human, and then veterinary species genomes. Genetic biomarkers called pharmacogenes have been identified as specific genetic loci on chromosomes which are associated with either positive or adverse drug responses. Pharmacogene variation may be classified according to the associated drug response, such as a change in (1) the pharmacokinetics; (2) the pharmacodynamics; (3) genes in the downstream pathway of the drug or (4) the effect of “off-target” genes resulting in a response that is unrelated to the intended target. There are many barriers to translation of pharmacogenetic information to the clinic, however, in human medicine, international initiatives are promising real change in the delivery of personalized medicine by 2025. We argue that for effective translation into the veterinary clinic, clinicians, international experts, and stakeholders must collaborate to ensure quality assurance and genetic test validation so that animals may also benefit from this genomics revolution.

Pharmacokinetic properties of tramadol and M1 metabolite in Northeast Brazilian donkeys (Equus asinus)

“…Indeed, the limitations in the design of the present study were that we did not randomize the allocation of treatment sequences. Consequently, given that we initially administered all animals with the lower dose and subsequently with the higher dose, it was not possible to differentiate the potential effects of metabolic induction from those of phenotype-based inter-subject variability (Campion & Dowell, 2019). As well as there is no quantification of the others tramadol metabolites (specially N-desmethyltramadol, M2), it is impossible an explanation for the non-linear M1 production and no proportionally increase in the parent compound between the doses in present study, so further studies are needed to quantify the others metabolites of tramadol and confirm the metabolism order in donkeys (Perez et al, 2016).With regard to adverse effects, we observed muscle spasms and ataxia in response to the administration of F I G U R E 3 Mean ratio of tramadol to M1 over a time course in eight healthy Northeast Brazilian donkeys, following intravenous administration of tramadol at 2 and 4 mg/kg both tramadol doses, although primarily with the 4 mg/kg dose.…”

A Review of the Important Role of CYP2D6 in Pharmacogenomics

“…However, the scale and implementation of veterinary pharmacogenomics remains limited to date. The primary example of veterinary pharmacogenomics is the identification of an ABCB1 (also known as MDR1 and encodes P-glycoprotein) allele that reduces the function of P-gp and has been associated with severe ADRs following administration of the anti-parasite drug, ivermectin, in homozygous individuals [118,119]. This variant is very common in specific canine breeds (e.g., collies and English shepherd dogs) due to selective breeding to historically desired traits, and highlights the requirement for veterinary pharmacogenomic research to go beyond broad species genetics and to target genetics at breed [118,120] and eventually individual level.…”

“…However, a few examples of CYP2D6 orthologue genotypes influencing drug metabolism have been studied. Canine and equine orthologues of human CYP2D6 are CYP2D15 and CYP2D50, respectively [118,121,122]. Four haplotypes have been identified in canine CYP2D15 (*1, *2, V1 and WT2), all of which have been shown to metabolise celecoxib at different rates in beagles and, additionally, the rate of metabolism of bufuralol was shown to be reduced in the WT2 haplotype [121].…”

Ivan Illich, Iatrogenesis and Pharmacogenetics

“…Pharmacogenetics associates variability to drug response to hereditary aspects after the identification of some pharmacogenes [47]. Pharmacogenomics is one of the first clinical applications of the post-genomic era and expands this dimension to even point to the development of personalized drugs [48].…”