Picolinic acid (PIC) is a byproduct of tryptophan catabolism through the kynurenine pathway, with anabolic effects on bone in vivo and in vitro. Hence, PIC has been nominated as a possible candidate to treat and/or prevent osteoporosis. However, the effective dose and toxicity of PIC are not known yet. To test the effect of escalating and very high doses of oral PIC, male Sprague-Dawley rats were gavaged PIC: Group 1 (n = 3) received incremental doses of 125, 250 and 500 mg/kg/day PIC on days 1, 3 and 5. Group 2 (n = 3) received 500 mg/kg BID (8 h apart; i.e. 1000 mg/kg/day) PIC on Day 1. Group 3 (n = 3) received 125 mg/kg/day PIC for seven consecutive days. Group 4 (n = 3) received 250 mg/kg/day PIC for seven consecutive days. Groups 1, 3 and 4 rats were euthanized on Day 8. Group 5 (n = 6) received 500 mg/kg/day PIC for two consecutive days and then once a week dose (Days 9, 16 and 23) of 500 mg/kg/dose PIC, until euthanasia (Day 30). Blood and cerebrospinal fluid (CSF) were sampled at euthanasia, and tissues showing abnormalities at necropsy underwent histopathology evaluation.

All rats displayed some degree of mild hypercalcemia and hyperkalemia. Rats receiving high doses (500 or 1000 mg/kg/day) of PIC died or were euthanized on humane grounds within the first week after showing clinical neurological signs, with animals later revealed to have brain necrosis and hemorrhage at histopathology. Rats receiving lower doses (125 or 250 mg/kg/day) of PIC completed treatment course without apparent clinical adverse events. In summary, very high doses of PIC (≥500 mg/kg/day) were vascular-neurotoxic. Possible future experiments must consider significantly lower doses.

吡啶甲酸 (PIC) 是色氨酸通过犬尿氨酸途径分解代谢的副产品，在体内和体外对骨骼具有合成代谢作用。因此，PIC 已被提名为治疗和/或预防骨质疏松症的可能候选药物。然而，PIC的有效剂量和毒性尚不清楚。为了测试递增和非常高剂量口服 PIC 的效果，雄性 Sprague-Dawley 大鼠被灌胃 PIC：第 1 组（n = 3）在第 1、3 天接受 125、250 和 500 mg/kg/天的递增剂量 PIC和 5.第 2 组（n = 3）在第 1 天接受 500 mg/kg BID（相隔 8 小时；即1000 mg/kg/天）PIC。第 3 组（n = 3）接受 125 mg/kg/天 PIC连续七天。第 4 组(n = 3) 连续 7 天接受 250 毫克/公斤/天的 PIC。第 1、3 和 4 组大鼠在第 8 天被安乐死。第 5 组（n = 6）连续两天接受 500 毫克/千克/天的 PIC，然后每周一次（第 9、16 和 23 天）500 毫克/千克/ kg/剂量 PIC，直至安乐死（第 30 天）。在安乐死时对血液和脑脊液 (CSF) 进行采样，并对尸检时显示异常的组织进行组织病理学评估。

所有大鼠均表现出一定程度的轻度高钙血症和高钾血症。接受高剂量（500 或 1000 毫克/千克/天）PIC 的大鼠在出现临床神经系统症状后的第一周内死亡或出于人道安乐死，随后在组织病理学上发现动物出现脑坏死和出血。接受较低剂量（125 或 250 毫克/公斤/天）的 PI​​C 的大鼠完成了治疗过程，没有明显的临床不良事件。总之，非常高剂量的 PIC（≥500 mg/kg/天）具有血管神经毒性。未来可能的实验必须考虑显着降低剂量。