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 (4 NP ) using rat liver homogenate and rat liver perfusion system. Methods Rat liver homogenate was incubated with 4 NP , which is mainly metabolized by cytochrome P 450 2 E 1, at 37, 34, 32 or 28°C. The M ichaelis constant ( K m ) and maximum elimination velocity ( V max ) of 4 NP were calculated by a H anes– W oolf plot. The hepatic extraction ratio ( E h ) of 4 NP was evaluated in a rat liver perfusion study at 37, 34, 32 or 28 °C . Moreover, the plasma concentration profiles of 4 NP 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 K m of 4 NP was not changed, the V max and E h were reduced at low temperatures. The plasma concentrations of 4 NP after its i.v. administration to rats were significantly increased at 28 °C . Conclusion Changes in the pharmacokinetics of 4 NP under hypothermic conditions were caused by alterations in V max and E h . We may be able to predict the disposition of a drug by in‐vitro studies.