Open AccessEvaluation for effect of hypothermia on the disposition of 4‐nitrophenol in rats by in‐vitro metabolism study and rat liver perfusion system
Author(s) -
Miyamoto Hirotaka,
Matsueda Satoshi,
Komori Kotaro,
Fumoto Shintaro,
Nakashima Mikiro,
Yoshikawa Naoki,
Hirata Haruna,
Shimokawa Kenta,
Ohwaki Yuichi,
Nishida Koyo
Publication year - 2013
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.12130
Subject(s) - pharmacokinetics , in vivo , perfusion , in vitro , elimination rate constant , chemistry , metabolism , kinetics , michaelis–menten kinetics , endocrinology , medicine , pharmacology , enzyme , biochemistry , biology , enzyme assay , volume of distribution , microbiology and biotechnology , physics , quantum mechanics
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.