Genetic Parameter Estimates for Metabolizing Two Common Pharmaceuticals in Swine

Abstract

In livestock, the regulation of drugs used to treat livestock has received increased attention and it is currently unknown how much of the phenotypic variation in drug metabolism is due to the genetics of an animal. Therefore, the objective of the study was to determine the amount of phenotypic variation in fenbendazole and flunixin meglumine drug metabolism due to genetics. The population consisted of crossbred female and castrated male nursery pigs (n = 198) that were sired by boars represented by four breeds. The animals were spread across nine batches. Drugs were administered intravenously and blood collected a minimum of 10 times over a 48 h period. Genetic parameters for the parent drug and metabolite concentration within each drug were estimated based on pharmacokinetics (PK) parameters or concentrations across time utilizing a random regression model. The PK parameters were estimated using a non-compartmental analysis. The PK model included fixed effects of sex and breed of sire along with random sire and batch effects. The random regression model utilized Legendre polynomials and included a fixed population concentration curve, sex, and breed of sire effects along with a random sire deviation from the population curve and batch effect. The sire effect included the intercept for all models except for the fenbendazole metabolite (i.e., intercept and slope). The mean heritability across PK parameters for the fenbendazole and flunixin meglumine parent drug (metabolite) was 0.15 (0.18) and 0.31 (0.40), respectively. For the parent drug (metabolite), the mean heritability across time was 0.27 (0.60) and 0.14 (0.44) for fenbendazole and flunixin meglumine, respectively. The errors surrounding the heritability estimates for the random regression model were smaller compared to estimates obtained from PK parameters. Across both the PK and plasma drug concentration across model, a moderate heritability was estimated. The model that utilized the plasma drug concentration across time resulted in estimates with a smaller standard error compared to models that utilized PK parameters. The current study found a low to moderate proportion of the phenotypic variation in metabolizing fenbendazole and flunixin meglumine that was explained by genetics in the current study.

Pharmacokinetics of Intravenous, Intramuscular, Oral, and Transdermal Administration of Flunixin Meglumine in Pre-wean Piglets

“…Additionally, our estimated V ss is consistent with previously reported values in swine ( 23 ). The heritability of the pigs was not within the scope of this project, however, a previous study has shown that heritability can have an effect on FM PK parameters, which may explain the two drug metabolism groups ( 30 ). Additionally, the stress that can be induced by repeated blood collections, individual housing, and early weaning could contribute to differences in drug metabolism ( 31 ).…”

“…Plasma concentration axes were scaled by ln ("plasma concentration" + 1) to improve resolution of plasma concentrations close to zero, as previously described (19). study has shown that heritability can have an effect on FM PK parameters, which may explain the two drug metabolism groups (30). Additionally, the stress that can be induced by repeated blood collections, individual housing, and early weaning could contribute to differences in drug metabolism (31).…”

The Pig as a Translational Animal Model for Biobehavioral and Neurotrauma Research

“…Pigs also exhibit many human-relevant behaviors, such as social structure, enabling the investigation of complex cognitive functions that are often impaired in human neurological disorders such as learning, memory, and social behavior [ 32 , 33 , 34 ]. Moreover, the pig’s physiology and metabolism are closer to humans compared to smaller animal models, enabling a more accurate evaluation of pharmacokinetics and treatment responses [ 35 , 36 ]. Collectively, these factors make the pig a valuable model for studying human neurological conditions and injury, facilitating the translation of preclinical findings to clinical applications, and enhancing our understanding of these complex disorders.…”