Change in pharmacokinetics of model compounds with different elimination processes in rats during hypothermia

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 (PSP), 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 1 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.