Evaluation of changes in hepatic disposition of phenolsulfonphthalein, indocyanine green and fluorescein isothiocyanate-dextran at low temperatures using a rat liver perfusion system

Objectives The aim of this study was to determine the factor changing the hepatic disposition of a drug during hypothermia using a rat liver perfusion system. Methods The livers of male Wistar rats were perfused at 37, 32 or 28°C in the single-pass mode. Venous outflow dilution patterns and biliary excretion rate patterns of phenolsulfonphthalein (PSP), indocyanine green (ICG) and fluorescein isothiocyanate (FITC)-dextran (FD-4, MW 4400) after the injection of a bolus into the perfused rat liver were analysed based on statistical moment theory. Key findings The first-pass extraction ratio (E h) of PSP was significantly decreased at 32 and 28°C compared with 37°C. The biliary recovery of PSP and its conjugate was decreased and the biliary excretion was kept at a high concentration and was prolonged by low perfusion temperatures. ICG was almost extracted by a single-pass through the liver even at 32 and 28°C. The biliary recovery of ICG was significantly decreased at low temperature. Although the distribution volume of FD-4 as a vascular reference was not changed by perfusion temperature, the E h of FD-4 was decreased at 28°C although not markedly. Conclusion The change in hepatic disposition of a drug at low perfusion temperatures differed according to disposition processes under hypothermia

Evaluation for effect of hypothermia on the disposition of 4-nitrophenol in rats by in-vitro metabolism study and rat liver perfusion system

Objectives The aim of this study was to evaluate the effect of hypothermia on the in-vivo pharmacokinetics of 4-nitrophenol (4NP) using rat liver homogenate and rat liver perfusion system. Methods Rat liver homogenate was incubated with 4NP, which is mainly metabolized by cytochrome P450 2E1, at 37, 34, 32 or 28°C. The Michaelis constant (Km) and maximum elimination velocity (Vmax) of 4NP were calculated by a Hanes-Woolf plot. The hepatic extraction ratio (Eh) of 4NP was evaluated in a rat liver perfusion study at 37, 34, 32 or 28°C. Moreover, the plasma concentration profiles of 4NP after its intravenous (i.v.) administration to rats were analysed by the moment theory and were compared with in-vitro parameters. Key findings While the Km of 4NP was not changed, the Vmax and Eh were reduced at low temperatures. The plasma concentrations of 4NP after its i.v. administration to rats were significantly increased at 28°C. Conclusion Changes in the pharmacokinetics of 4NP under hypothermic conditions were caused by alterations in Vmax and E h. We may be able to predict the disposition of a drug by in-vitro studies