Change in pharmacokinetics of model compounds with different elimination processes in rats during hypothermia
Change in pharmacokinetics of model compounds with different elimination processes in rats during hypothermia
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DOI：
10.1248/bpb.30.1763
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发表时间：
2007-09-01
影响因子：
2
通讯作者：
Sakaeda, Toshiyuki
中科院分区：
文献类型：
--
作者：
Nishida, Koyo;Okazaki, Madoka;Sakaeda, Toshiyuki
我们比较了不同消除过程的模型化合物在低温和常温大鼠体内的药代动力学，以获得低温过程中药物治疗的基本信息。用戊巴比妥钠麻醉雄性Wistar大鼠，热灯恒温37℃（常温组），外冷32℃或28℃（低温组）。我们选择了苯酚磺酞（PSIP）、吲哚菁绿（ICG）和异硫氰酸荧光素(FITC)-葡聚糖（FD-4, Mw 4400）作为模型化合物来确定低温治疗期间清除途径的变化。与恒温组（37℃）相比，低温组（32℃、28℃）静脉给药1 mg后，血浆中胆道、泌尿和代谢消除型PSP浓度显著升高。低温组的PSP清除率（胆汁、尿液和代谢物）均下降，表明低温对主动消除过程有影响。在温度为28℃时，ICG作为胆道排泄型，经1 mg低温大鼠静脉注射后血浆浓度高于正常大鼠，全身总清除率降低50%以上。另一方面，FD-4作为尿排泄类型在37℃和32℃时的静脉药代动力学几乎没有差异，但在28℃时，FD-4的肾脏清除率明显降低。因此，在低温组中药物的药代动力学变化可能随着消除过程的不同而不同。
We compared the pharmacokinetics of model compounds with different elimination processes between hypothermic and normothermic rats, to obtain basic information concerning drug therapy during hypothermia. Male Wistar rats were anesthetized with sodium pentobarbital and kept at temperatures of 37 degrees C (normothermic group) by heat lamp, and 32 degrees C or 28 degrees C (hypothermic group) by external cooling. We chose phenolsulfonphthalein (PSIP), indocyanine green (ICG) and fluorescein isothiocyanate (FITC)-dextran (FD-4, Mw 4400) as model compounds to determine changes in clearance pathways during hypothermia therapy. The plasma concentrations of PSP as biliary, urinary and metabolic elimination type were increased significantly in the hypothermic group (32 degrees C, 28 degrees C) after i.v. administration at a dose of 1 mg, compared to the normothermic group (37 degrees C). Each PSP clearance (bile, urine and metabolites) in the hypothermic group was decreased, suggesting an influence of hypothermia on the active elimination process. The decreasing tendency was marked at a temperature of 28 degrees C. Moreover, the plasma concentrations of ICG as the biliary excretion type after i.v. administration to the hypothermic rats at a dose of I mg were higher with more than 50% decrease in the total body clearance compared to normothermic rats. On the other hand, there was almost no difference in the i.v. pharmacokinetics of FD-4 as the urinary excretion type between 37 degrees C and 32 degrees C. However, renal clearance of FD-4 was significantly decreased at a temperature of 28 degrees C. Accordingly, the change in pharmacokinetics of a drug in the hypothermic group could differ with the elimination processes.