Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Pretoria.
Onderstepoort J Vet Res. 2022 Jun 14;89(1):e1-e8. doi: 10.4102/ojvr.v89i1.1978.
Diclofenac was responsible for the decimation of Gyps vulture species on the Indian subcontinent during the 1980s and 1990s. Gyps vultures are extremely sensitive (the lethal dose 50 [LD50] ~ 0.1 mg/kg - 0.2 mg/kg), with toxicity appearing to be linked to metabolic deficiency, demonstrated by the long T1/2 (~12 h - 17 h). This is in striking comparison to the domestic chicken (Gallus gallus domesticus), in which the LD50 is ~10 mg/kg and the T1/2 is ~1 h. The phase 1 cytochrome P450 (CYP) 2C subfamily has been cited as a possible reason for metabolic deficiency. The aim of this study was to determine if CYP2C9 homolog pharmacogenomic differences amongst avian species is driving diclofenac toxicity in Gyps vultures. We exposed each of 10 CYP-inhibited test group chickens to a unique dose of diclofenac (as per the Organisation for Economic Co-operation and Development [OECD] toxicity testing guidelines) and compared the toxicity and pharmacokinetic results to control group birds that received no CYP inhibitor. Although no differences were noted in the LD50 values for each group (11.92 mg/kg in the CYP-inhibited test group and 11.58 mg/kg in the control group), the pharmacokinetic profile of the test group was suggestive of partial inhibition of CYP metabolism. Evaluation of the metabolite peaks produced also suggested partial metabolic inhibition in test group birds, as they produced lower amounts of metabolites for one of the three peaks demonstrated and had higher diclofenac exposure. This pilot study supports the hypothesis that CYP metabolism is varied amongst bird species and may explain the higher resilience to diclofenac in the chicken versus vultures.
双氯芬酸在 20 世纪 80 年代和 90 年代导致了印度次大陆的食羊鹰属物种大量减少。食羊鹰属非常敏感（半数致死剂量 [LD50]约为 0.1 毫克/千克-0.2 毫克/千克），毒性似乎与代谢缺陷有关，表现为较长的半衰期（~12 小时-17 小时）。这与家鸡（Gallus gallus domesticus）形成鲜明对比，家鸡的 LD50约为 10 毫克/千克，半衰期约为 1 小时。第一阶段细胞色素 P450（CYP）2C 亚家族被认为是代谢缺陷的可能原因。本研究旨在确定禽类 CYP2C9 同源物的药物基因组差异是否导致食羊鹰属对双氯芬酸的毒性。我们使每组 10 只 CYP 受抑制的实验组鸡暴露于独特剂量的双氯芬酸（按照经济合作与发展组织 [OECD]毒性测试指南），并将毒性和药代动力学结果与未接受 CYP 抑制剂的对照组鸟类进行比较。虽然每组的 LD50值没有差异（实验组为 11.92 毫克/千克，对照组为 11.58 毫克/千克），但实验组的药代动力学特征表明 CYP 代谢受到部分抑制。对产生的代谢物峰的评估也表明实验组鸟类的代谢受到部分抑制，因为它们产生的三种峰之一的代谢物较少，并且双氯芬酸暴露量较高。这项初步研究支持了 CYP 代谢在鸟类物种中存在差异的假设，并可能解释了鸡对双氯芬酸的抵抗力高于秃鹫的原因。
