Fukuyama T, Yamaoka K, Tabata K, Nakagawa T
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Biol Pharm Bull. 1995 Feb;18(2):251-5. doi: 10.1248/bpb.18.251.
The effect of the acute hepatic failure induced by CCl4 on the pharmacokinetics of diclofenac, which is definitely subject to enterohepatic circulation (EHC) in normal rats, was evaluated. This hepatic failure extinguished the secondary peak on the plasma time course which is usually observed in normal rats due to EHC. In the group without EHC by means of bile cannulation, the total clearance (CL) markedly decreased by CCl4-intoxication from 0.7 l/h/kg down to 0.1 l/h/kg, and mean residence time (MRT) increased from 0.29 h up to 2.8 h. The plasma time curves of the rats with laparotomy and with bile duct-cannulation were almost the same in the CCl4-intoxicated group. The bile excretion ratio of diclofenac markedly decreased by CCl4-intoxication from 43% down to 13%. In both groups, 92% of the total diclofenac excreted into the bile was glucuronide. While EHC made area under the curve (AUC) and MRT obviously increase in the CCl4-free rats, the effect of EHC on these moments was negligible in the CCl4-intoxicated rats. In the CCl4-intoxicated condition, the elimination of diclofenac in the rats with laparotomy was considerably slower than that in the rats without laparotomy. The plasma time courses were obviously monoexponential in the former group, while those were almost biexponential in the latter group.
评估了四氯化碳诱导的急性肝衰竭对双氯芬酸药代动力学的影响，双氯芬酸在正常大鼠中肯定会进行肠肝循环（EHC）。这种肝衰竭消除了血浆时间进程中的第二个峰，该峰在正常大鼠中通常由于肠肝循环而出现。在通过胆管插管消除肠肝循环的组中，四氯化碳中毒使总清除率（CL）从0.7升/小时/千克显著降低至0.1升/小时/千克，平均驻留时间（MRT）从0.29小时增加至2.8小时。在四氯化碳中毒组中，开腹大鼠和胆管插管大鼠的血浆时间曲线几乎相同。四氯化碳中毒使双氯芬酸的胆汁排泄率从43%显著降低至13%。在两组中，排泄到胆汁中的双氯芬酸总量的92%是葡糖醛酸结合物。虽然肠肝循环在无四氯化碳的大鼠中使曲线下面积（AUC）和MRT明显增加，但在四氯化碳中毒的大鼠中，肠肝循环对这些参数的影响可忽略不计。在四氯化碳中毒状态下，开腹大鼠中双氯芬酸的消除明显慢于未开腹大鼠。前一组的血浆时间进程明显呈单指数形式，而后者的血浆时间进程几乎呈双指数形式。
