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- Title
Evaluation for effect of hypothermia on the disposition of 4-nitrophenol in rats by in-vitro metabolism study and rat liver perfusion system.
- Authors
Miyamoto, Hirotaka; Matsueda, Satoshi; Komori, Kotaro; Fumoto, Shintaro; Nakashima, Mikiro; Yoshikawa, Naoki; Hirata, Haruna; Shimokawa, Kenta; Ohwaki, Yuichi; Nishida, Koyo
- Abstract
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 P450 2 E1, at 37, 34, 32 or 28°C. The Michaelis constant ( Km) and maximum elimination velocity ( Vmax) of 4 NP were calculated by a Hanes- Woolf plot. The hepatic extraction ratio ( Eh) 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 Km of 4 NP was not changed, the Vmax and Eh 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 Vmax and Eh. We may be able to predict the disposition of a drug by in-vitro studies.
- Subjects
HYPOTHERMIA -- Risk factors; NITROPHENOLS; RATS; METABOLISM; PHARMACOKINETICS; LOW temperatures; EDUCATION
- Publication
Journal of Pharmacy & Pharmacology, 2013, Vol 65, Issue 10, p1536
- ISSN
0022-3573
- Publication type
Article
- DOI
10.1111/jphp.12130