THE EFFECT OF LIVER DYSFUNCTION ON COLCHICINE PHARMACOKINETICS IN THE RAT
THE EFFECT OF LIVER DYSFUNCTION ON COLCHICINE PHARMACOKINETICS IN THE RAT
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DOI：
10.1002/hep.1840110209
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发表时间：
1990-02-01
期刊：
影响因子：
13.5
通讯作者：
SPEEG, KV
中科院分区：
文献类型：
--
作者：
LEIGHTON, JA;BAY, MK;SPEEG, KV
最近的研究表明，秋水仙碱可能对原发性胆汁性或酒精性肝硬化患者有益。然而，对其在肝功能受损的情况下的药代动力学知之甚少。为了研究这一点，我们研究了三种实验性肝功能障碍模型和一种细胞色素 P-450 抑制对大鼠秋水仙碱消除的影响。实验性肝功能障碍模型包括胆管结扎（假手术对照）、α-异硫氰酸萘酯诱导的肝内胆汁淤积和半乳糖胺诱导的弥漫性肝细胞坏死。对照组的秋水仙碱清除率为77.33ml/min.cntdot。公斤.+-. 8.27 毫升/分钟.cntdot。 kg，半衰期为 16.68 分钟.+-。 0.97 分钟，分布容积为 1.84 L/kg .+-。 0.15升/公斤。在秋水仙碱给药前 15 分钟腹腔注射西咪替丁 120 mg/kg，导致清除率降低 32% (p < 0.05)，半衰期增加 38% (p < 0.05)。分布量没有变化。胆管结扎后 48 小时，秋水仙碱清除率下降 84% (p < 0.05)，终末半衰期增加至 513.7 分钟.+-。 106.6 分钟 (p < 0.05)，分布容积增加 175% (p < 0.05)。假手术大鼠中秋水仙碱的药代动力学与上述对照组没有统计学差异。给予α-萘基异硫氰酸酯后，秋水仙碱清除率降低55％(p＜0.05)，半衰期增加56％(p＜0.05)并且分布体积减少30％(p＜0.05)。给予半乳糖胺 1,000 mg/kg 后，秋水仙碱清除率下降 62% (p < 0.05)，半衰期增加至 144.72 分钟.+-。 35.30 分钟 (p < 0.05)，分布容积增加 124% (p < 0.05)。这些数据表明，大鼠的实验性肝损伤显着损害秋水仙碱的药代动力学。他们还支持肝脏是秋水仙碱消除的主要途径的假设。
Recent work has shown that colchicine may benefit patients with primary biliary or alcoholic cirrhosis. However, very little is known about its pharmacokinetics in the presence of impaired liver function. To study this we examined the effects of three models of experimental liver dysfunction and one of cytochrome P-450 inhibition on colchicine elimination in the rat. The models of experimental liver dysfunction included bile duct ligation (with sham-operated controls), .alpha.-naphthylisothiocyanate-induced intrahepatic cholestasis and galactosamine-induced diffuse hepatocellular necrosis. The control group had a colchicine clearance of 77.33 ml/min .cntdot. kg .+-. 8.27 ml/min .cntdot. kg, a half-life of 16.68 min .+-. 0.97 min and a volume of distribution of 1.84 L/kg .+-. 0.15 L/kg. Cimetidine administration, 120 mg/kg intraperitoneally 15 min before colchicine administration, caused clearance to decrease by 32% (p < 0.05) and half-life to increase by 38% (p < 0.05). Volume of distribution did not change. At 48 hr after bile duct ligation, colchicine clearance decreased by 84% (p < 0.05), terminal half-life increased to 513.7 min .+-. 106.6 min (p < 0.05) and volume of distribution increased by 175% (p < 0.05). Colchicine pharmacokinetics in sham-operated rats were not statistically different from the above mentioned controls. After .alpha.-naphthylisothiocyanate administration, colchicine clearance decreased by 55% (p < 0.05), the half-life increased by 56% (p < 0.05) and the volume of distribution decreased by 30% (p < 0.05). After administration of galactosamine, 1,000 mg/kg, colchicine clearance decreased by 62% (p < 0.05), half-life increased to 144.72 min .+-. 35.30 min (p < 0.05) and volume of distribution increased by 124% (p < 0.05). These data show that experimental hepatic injury in the rat significantly impairs colchicine pharmacokinetics. They also support the hypothesis that the liver is a major route of colchicine elimination.