Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous Cidofovir in cynomolgus monkeys
Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous Cidofovir in cynomolgus monkeys
复制标题
DOI：
10.1006/toxs.1998.2481
复制
发表时间：
1998-08-01
影响因子：
3.8
通讯作者：
Cundy, KC
中科院分区：
文献类型：
--
作者：
Lacy, SA;Hitchcock, MJM;Cundy, KC
在动物和人类中，静脉注射抗病毒核苷酸类似物西多福韦会导致剂量限制性肾毒性，其特征是近端肾小管上皮细胞受损。Probenecid是近端小管上皮细胞中有机阴离子运输的竞争性抑制剂，研究了其对西多福韦的慢性毒性和药代动力学的影响。食蟹猴（5只/性别/组）连续52周静脉注射西多福韦，剂量分别为0（生理盐水）、0.1、0.5或2.5 mg/kg/剂，或2.5 mg/kg/剂与probenecid联合（在西多福韦给药前1小时口服30 mg/kg/剂）。西多福韦相关的组织病理学改变仅见于肾脏、睾丸和附睾。肾毒性（轻度至中度皮质小管上皮细胞核肿大，小管扩张，基底膜增厚）仅存在于接受2.5 mg/kg剂量的西多福韦不含苯丙酸的猴子中。以2.5 mg/kg/剂量单独或与口服probenecid联合给予西多福韦的猴子，睾丸（低密度和aspermatgenesis）和附睾（严重少密度和aspermia）变化的发生率和严重程度增加。在第1周至第52周期间，2.5 mg/kg剂量组的肾脏药物清除率降低，并导致西多福韦全身暴露量增加（通过AUG测量），单独给药西多福韦的猴子（雄性增加312%，雌性增加98%）明显高于联合给药的猴子（雄性增加32%，雌性增加3%）。这些结果表明，口服丙戊酸联合给药可以保护接受慢性静脉注射西多福韦治疗的猴子免受肾毒性和伴随的肾脏清除率下降的形态学证据。(C) 1998毒理学学会。
In animals and humans, intravenous administration of the antiviral nucleotide analogue cidofovir results in a dose-limiting nephrotoxicity characterized by damage to the proximal tubular epithelial cells. Probenecid, a competitive inhibitor of organic anion transport in the proximal tubular epithelial cells, was evaluated for its effect on the chronic toxicity and pharmacokinetics of cidofovir. Cynomolgus monkeys (5/sex/group) received cidofovir for 52 consecutive weeks as a once weekly intravenous bolus injection at 0 (saline), 0.1, 0.5, or 2.5 mg/kg/dose alone or at 2.5 mg/kg/dose in combination with probenecid (30 mg/kg/dose via oral gavage 1 h prior to cidofovir administration). Cidofovir-associated histopathological changes were seen only in the kidneys, testes, and epididymides. Nephrotoxicity (mild to moderate cortical tubular epithelial cell karyomegaly, tubular dilatation, basement membrane thickening) was present only in monkeys receiving 2.5 mg/kg/dose cidofovir without probenecid. The incidence and severity of testicular (hypo- and aspermatogenesis) and epididymal (severe oligo- and aspermia) changes were increased in monkeys administered cidofovir at 2.5 mg/kg/dose, either alone or in combination with oral probenecid, Renal drug clearance was decreased between Weeks 1 and 52 in the 2.5 mg/kg/dose groups and resulted in an increased systemic exposure to cidofovir las measured by AUG) that was significantly greater in monkeys administered cidofovir alone (312% increase in males, 98% in females) than in those coadministered probenecid (32% increase in males, 3% in females). These results demonstrate that oral probenecid coadministration protects against the morphological evidence of nephrotoxicity and the accompanying decrease in renal clearance in monkeys receiving chronic intravenous cidofovir treatment. (C) 1998 Society of Toxicology.