Koehn S, Frey F J, Speck R F, Zeugin T, Schaffner T, Zimmermann A, Frey B M
Medizinische Poliklinik, Inselspital, University of Berne, Switzerland.
J Pharmacokinet Biopharm. 1990 Oct;18(5):381-99. doi: 10.1007/BF01061701.
Since oxidation plays a key role in the metabolism of cyclosporine A (CsA), the pharmacokinetics and the toxicity of CsA was investigated in female dark Agouti rats exhibiting a deficiency for debrisoquine hydroxylation and for dextromethorphan demethylation. When compared with Wistar rats (n = 10), dark Agouti rats (n = 10) had a higher mean clearance (4.8 ml/min per kg vs. 3.3 ml/min per kg) and a lower mean residence time (606 min vs. 1361 min) after intravenous dosing of CsA. The systemic availability of subcutaneous CsA was close to 100%. The steady state CsA concentrations assessed by HPLC in whole blood after subcutaneous dosing of 20 mg/kg per day for 23 days (n = 10) were about 1000 ng/ml in dark Agouti rats. When compared with dark Agouti rats treated with cremophore (n = 10) or not treated at all (n = 12), dark Agouti rats on chronic subcutaneous CsA plus cremophore for 23 days (n = 10) had no difference in kidney histology but had slightly increased liver fatty changes. Rats on CsA and/or cremophore had a decreased uric acid clearance and evidence of hypoaldosteronism. The urinary ratio of debrisoquine/4-hydroxydebrisoquine decreased in rats on CsA, whereas the O-demethylation and N-demethylation of liver obtained from rats on cremophore was impaired. Thus, dark Agouti rats show no difference in the metabolism of CsA and when given CsA for 23 days show drug-induced functional but no relevant structural light microscopic changes in the kidney, and functional and slight structural changes in the liver.
由于氧化在环孢素A（CsA）的代谢中起关键作用，因此在表现出异喹胍羟化和右美沙芬去甲基化缺陷的雌性深色刺豚鼠中研究了CsA的药代动力学和毒性。与Wistar大鼠（n = 10）相比，深色刺豚鼠（n = 10）在静脉注射CsA后具有更高的平均清除率（4.8 ml/min per kg对3.3 ml/min per kg）和更低的平均驻留时间（606分钟对1361分钟）。皮下注射CsA的全身可用性接近100%。在23天内每天皮下注射20 mg/kg（n = 10）后，通过HPLC评估的深色刺豚鼠全血中CsA的稳态浓度约为1000 ng/ml。与用聚氧乙烯蓖麻油处理（n = 10）或未处理（n = 12）的深色刺豚鼠相比，慢性皮下注射CsA加聚氧乙烯蓖麻油23天的深色刺豚鼠（n = 10）肾脏组织学无差异，但肝脏脂肪变化略有增加。接受CsA和/或聚氧乙烯蓖麻油的大鼠尿酸清除率降低，并有醛固酮减少的证据。服用CsA的大鼠中异喹胍/4-羟基异喹胍的尿比值降低，而从服用聚氧乙烯蓖麻油的大鼠肝脏中获得的O-去甲基化和N-去甲基化受损。因此，深色刺豚鼠在CsA的代谢上没有差异，并且在给予CsA 23天后，在肾脏中显示出药物诱导的功能性但无相关的结构光镜变化，在肝脏中显示出功能性和轻微的结构变化。
