KuKanich Butch, KuKanich Kate
Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA.
Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA.
Vet Anaesth Analg. 2015 Nov;42(6):597-607. doi: 10.1111/vaa.12257. Epub 2015 Mar 2.
To assess the effects of cytochrome P450 (CYP) inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) in various combinations on the pharmacokinetics of oral methadone in Greyhound dogs to determine the specific effects of the different inhibitors and if a clinically relevant interaction occurs.
Non-randomized, sequential design.
Six healthy Greyhound dogs (three male, three female).
Canine CYP inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) were administered in varying combinations prior to the administration of oral methadone. Plasma was obtained from each dog to enable the determination of methadone and CYP inhibitor drug concentrations using liquid chromatography with either mass spectrometry or ultraviolet detection.
Significant increases in the area under the curve (AUC) and maximum plasma concentrations (CMAX ) of methadone occurred in all groups administered chloramphenicol. The AUC (6 hours ng mL(-1)) and CMAX (6 ng mL(-1)) of methadone significantly increased to 541 hours ng mL(-1) and 47.8 ng mL(-1), respectively, when methadone was administered with chloramphenicol as a sole inhibitor. There were no significant effects of CYP inhibitors other than chloramphenicol on methadone pharmacokinetics, which suggests that chloramphenicol was primarily responsible for the pharmacokinetic interaction.
This study demonstrated significant effects of chloramphenicol on the pharmacokinetics of oral methadone. Further studies should investigate the effects of chloramphenicol on methadone pharmacokinetics in multiple dog breeds and examine whether oral methadone would be an effective analgesic in dogs. In addition, the safety of chloramphenicol and its effects on the pharmacokinetics of parenteral methadone warrant assessment.
评估细胞色素P450（CYP）抑制剂（酮康唑、氯霉素、甲氧苄啶、氟西汀、西咪替丁和美托咪定）不同组合对灵缇犬口服美沙酮药代动力学的影响，以确定不同抑制剂的具体作用以及是否发生临床相关相互作用。
非随机、序贯设计。
6只健康灵缇犬（3只雄性，3只雌性）。
在口服美沙酮之前，以不同组合给予犬用CYP抑制剂（酮康唑、氯霉素、甲氧苄啶、氟西汀、西咪替丁和美托咪定）。从每只犬采集血浆，以便使用液相色谱结合质谱或紫外检测法测定美沙酮和CYP抑制剂药物浓度。
所有给予氯霉素的组中美沙酮的曲线下面积（AUC）和最大血浆浓度（CMAX）均显著增加。当美沙酮与氯霉素作为唯一抑制剂合用时，美沙酮的AUC（6小时ng mL⁻¹）和CMAX（6 ng mL⁻¹）分别显著增加至541小时ng mL⁻¹和47.8 ng mL⁻¹。除氯霉素外，其他CYP抑制剂对美沙酮药代动力学无显著影响这表明氯霉素是药代动力学相互作用的主要原因。
本研究证明氯霉素对口服美沙酮的药代动力学有显著影响。进一步的研究应调查氯霉素对多种犬种美沙酮药代动力学的影响，并检查口服美沙酮在犬中是否为有效的镇痛药。此外，氯霉素的安全性及其对胃肠外美沙酮药代动力学的影响值得评估。
