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

Miyamoto, Hirotaka; Matsueda, Satoshi; Komori, Kotaro; Fumoto, Shintaro; Nakashima, Makoto; Yoshikawa, Naoki; Hirata, Haruna; Shimokawa, Kenta; Ohwaki, Yuichi; Nishida, Koyo

doi:10.1111/jphp.12130

Cited by 2 publications

(1 citation statement)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the concentration of midazolam at 0 min estimated by analyses of a two-compartment model was increased slightly under hypothermia ( Figure 2) and the distribution volume of the central compartment (V c ) was significantly lower at 28°C than at 37°C (data not shown). In our previous study, the initial concentrations of several drugs (phenolsulfonphthalein, indocyanine green, fluorescein isothiocyanate-dextran, 4-nitrophenol) after intravenous injection were also increased according to body temperature [31,32]. Tveita et al reported that the blood volume and the plasma volume were decreased post-hypothermia [33].…”

Section: Discussionmentioning

confidence: 87%

Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats

Miyamoto

Matsueda

Moritsuka

et al. 2015

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

The effect of hypothermia on the in vivo pharmacokinetics of midazolam was evaluated, with a focus on altered metabolism in the liver and binding to serum proteins. Rat primary hepatocytes were incubated with midazolam (which is metabolized mainly by CYP3A2) at 37, 32 or 28 °C. The Michaelis-Menten constant (Km) and maximum velocity (Vmax) of midazolam were estimated using the Michaelis-Menten equation. The Km of CYP3A2 midazolam remained unchanged, but the Vmax decreased at 28 °C. In rats, whose temperature was maintained at 37, 32 or 28 °C by a heat lamp or ice pack, the plasma concentrations of midazolam were higher, whereas those in the brain and liver were unchanged at 28 °C. The tissue/plasma concentration ratios were, however, increased significantly. The unbound fraction of midazolam in serum at 28 °C was half that at 37 °C. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding.

show abstract

Section: Discussionmentioning

confidence: 87%

Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats

Miyamoto

Matsueda

Moritsuka

et al. 2015

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

show abstract

Optimization of Drug Administration in Special Populations Focusing on Drug Distribution

Miyamoto

2024

YAKUGAKU ZASSHI

View full text Add to dashboard Cite

Patients with special backgrounds such as organ dysfunction, elderly individuals, children, and pregnant or nursing women in whom the pharmacokinetics of an agent are expected to differ from those observed in the general patient population, are referred to as special populations. Administration of drug therapy to these patients warrants close attention to and knowledge of altered pharmacokinetics to design appropriate personalized dosing regimens. In this study, we investigated the effects of hypothermia and renal impairment on drug pharmacokinetics, focusing on tissue distribution. Analysis of the effects of hypothermia on local liver kinetics of drugs revealed decreased activity of drug-metabolizing enzymes and transporters. Furthermore, we investigated in vivo drug pharmacokinetics and observed that blood drug concentrations increased with a decrease in the body temperature. However, the tissue concentration of midazolam (MDZ) remained unchanged even with a decrease in body temperature, which indicates reduced tissue transfer of MDZ. With regard to the effect of renal impairment, blood concentration of MDZ decreased in patients with acute renal failure and increased in those with chronic renal failure. However, MDZ clearance was decreased in patients with chronic renal failure owing to decreased expression of hepatic metabolic enzymes and reduced hepatic blood flow. This study highlights that tissue translocation of drugs differs across special populations and that optimization of drug administration based on the prediction of tissue concentrations is important.

show abstract

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

Abstract: Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, 10Nagasaki 852-8521, Japan

Cited by 2 publications

References 23 publications

Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats

Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats

Optimization of Drug Administration in Special Populations Focusing on Drug Distribution

Contact Info

Product

Resources

About