Batty Kevin T, Moore Brioni R, Stirling Verity, Ilett Kenneth F, Page-Sharp Madhu, Shilkin Keith B, Mueller Ivo, Karunajeewa Harin A, Davis Timothy M E
School of Pharmacy, Curtin University of Technology, Bentley, Western Australia, Australia.
Toxicology. 2008 Jul 10;249(1):55-61. doi: 10.1016/j.tox.2008.04.004. Epub 2008 Apr 16.
Pharmacokinetic and toxicological data for piperaquine (PQ) - a bisquinoline antimalarial drug - are limited, despite strong evidence of clinical efficacy. Our aim was to conduct a detailed toxicological investigation of PQ in Swiss mice. The study comprised three phases: (i) oral PQ phosphate (PQP) at doses ranging from 0 to 600 mg/(kg day) for 5 days. Pathology tests included haematological and biochemical indices, and histopathology of the liver, heart and kidneys. (ii) PQP doses of 0-300 mg/(kg day) for 12 days and pathology tests as described. (iii) Pharmacokinetic parameters determined from mice given 100mg/(kg day) PQP for 5 days. Blood was harvested from mice over 56 days and plasma analysed by HPLC. Mice given low doses of PQ had stable, normal body and organ weights. Weight loss was observed in mice given high doses and was accompanied by increased liver and kidney weights. Principal haematological effects were modest fluctuations in total white cells and neutrophils; biochemical effects were elevated ALT and low albumin in high-dose groups. Liver histopathology revealed minor cytoplasmic and inflammatory effects. PQ treatment did not affect heart muscle but minor renal changes were observed at high doses. Pharmacokinetic parameters were consistent with previous studies: t1/2, CL and V were 16 days, 1.36 L/(h kg) and 756 L/kg, respectively. PQ may cause minor hepatotoxicity and renal tubular cell damage, and adversely affect selected haematological indices, as demonstrated at cumulative doses approximately 50 times those recommended in humans. Significant effects in humans will likely be infrequent and dose-related.
尽管双喹啉抗疟药磷酸哌喹（PQ）有确凿的临床疗效证据，但其药代动力学和毒理学数据有限。我们的目的是对瑞士小鼠进行PQ的详细毒理学研究。该研究包括三个阶段：（i）口服磷酸哌喹（PQP），剂量范围为0至600毫克/（千克·天），持续5天。病理学测试包括血液学和生化指标，以及肝脏、心脏和肾脏的组织病理学检查。（ii）PQP剂量为0至300毫克/（千克·天），持续12天，并进行上述病理学测试。（iii）对给予100毫克/（千克·天）PQP持续5天的小鼠测定药代动力学参数。在56天内从小鼠采集血液，并用高效液相色谱法分析血浆。给予低剂量PQ的小鼠体重和器官重量稳定、正常。高剂量组小鼠出现体重减轻，并伴有肝脏和肾脏重量增加。主要血液学影响是白细胞总数和中性粒细胞有适度波动；高剂量组的生化影响是谷丙转氨酶升高和白蛋白降低。肝脏组织病理学显示有轻微的细胞质和炎症影响。PQ治疗不影响心肌，但高剂量时观察到轻微的肾脏变化。药代动力学参数与先前研究一致：半衰期、清除率和分布容积分别为16天、1.36升/（小时·千克）和756升/千克。PQ可能会引起轻微的肝毒性和肾小管细胞损伤，并对选定的血液学指标产生不利影响，如在累积剂量约为人类推荐剂量50倍时所显示的那样。在人类中产生显著影响可能并不常见，且与剂量相关。
