Comparative studies of midazolam metabolism in chickens, turkeys, ring-necked pheasant and bobwhite quail: In vitro, in vivo and physiologically-based pharmacokinetic modeling.

摘要

Comparatively little is known about the ability of commercially raised poultry and gamebirds to metabolize therapeutic drugs. The goal of this research was to use a combination of in vitro, in vivo and physiologically-based pharmacokinetic (PBPK) studies to characterize metabolism of a cytochrome P450 3A substrate in four closely related poultry and gamebird species.Cytochrome P450 3A (CYP3A) enzymes, found primarily in the liver but also in the kidneys and other organs of mammals, are one of the major oxidative metabolic pathways. Studies using hepatic microsomes from chickens, turkeys, pheasant and bobwhite quail were conducted with midazolam as a substrate of CYP3A metabolism. Inhibition of midazolam metabolism was also measured in vitro using ketoconazole as an inhibitor. All four avian species produced 1-hydroxymidazolam as the major metabolite and 4-hydroxymidazolam as a minor metabolite. Ketoconazole inhibited the 4-hydroxymidazolam more than the 1-hydroxymidazolam and pheasant and quail appeared most sensitive to inhibition.To better assess underlying metabolic processes in our four avian species, whole animal pharmacokinetic and tissue residue studies were conducted after midazolam intravenous administration. Pharmacokinetic profiles were similar with regard to area under the drug concentration-time curve. Tissue residue studies also resulted in similar profiles. There was some variation in the later time points for all tissues, with some birds clearing the drug faster than others. Due to the sparse nature of the pharmacokinetic data collected, a bootstrapping technique was employed to estimate pharmacokinetic parameters and an estimate of their variability within the study population.To obtain a more mechanistic understanding of hepatic metabolism in our avian species, a PBPK model was developed for the metabolism of midazolam in each species. This model was optimized for the chicken and then applied to the other species, changing only the body weights and organ volumes as appropriate. The PBPK model as designed for the chicken was surprisingly accurate at predicting midazolam tissue drug concentrations in the other species.