Acute Peripheral Inflammation Increases Plasma Concentration of Hypoglycemic Agent Nateglinide with Decreased Hepatic Drug-Metabolizing Activity in Rats

Kojina, Moeko; Suzuki, Keiichiro; Nishiwaki, Akane; Aiba, Tetsuya

doi:10.1248/bpb.b20-00677

Cited by 2 publications

(1 citation statement)

References 39 publications

(60 reference statements)

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“…[4][5][6] In addition to those effects on the unbound fraction, the renal impairments can decrease the hepatic drug metabolizing activity of therapeutic compounds, 1,7) to which proinflammatory mediators released from damaged tissues are reported to largely contribute. 8,9) The mediators, including interleukin-6 and tumor necrosis factor-α, activate the nuclear factor-kappaB and interfere with the heterodimerization of nuclear receptors. [10][11][12] Since the heterodimerization is an essential step for transactivation of genes of the hepatic drug metabolizing enzymes, the interference results in suppression of their protein expression and drug metabolizing activity.…”

Section: Introductionmentioning

confidence: 99%

Altered Pharmacological Efficacy of Phenobarbital with the Treatment of 7,8-Dihydroxyflavone, an Agonist of Tropomyosin Receptor Kinase B, in Rats

Suzuki

Matsumoto

Takenaka

et al. 2023

Biological & Pharmaceutical Bulletin

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From our previous observation that the anesthetic effects of phenobarbital potentiate in rats with a decreased cerebral protein expression of the potassium chloride cotransporter KCC2 (SLC12A5), an in vivo study was conducted to clarify whether the pharmacological effect of phenobarbital alters by stimulating the cerebral tropomyosin receptor kinase B (TrkB) that is known to down-regulate the KCC2 protein expression. The stimulation was performed in rats with repetitious intraperitoneal administration of a TrkB agonist, namely 7,8-dihydroxyflavone (DHF). After that, the rats underwent an intraventricular infusion of phenobarbital using a dwelled cannula, and the onset time of the phenobarbital-induced general anesthesia was determined. In addition, their brain tissues were excised and cerebral cortices were collected. Then, subcellular fractions were prepared and the cerebral expression of various proteins involving the anesthetic effects of phenobarbital was examined. It was demonstrated that phenobarbital induced general anesthesia about 2 times faster in rats receiving the DHF treatment than in control rats, and that the phenobarbital amount in the brain tissue at the onset time of anesthesia was lower in rats with the treatment. Western blotting showed that the cerebral protein expression of KCC2 decreases, and the phosphorylation of the TrkB protein increases with the DHF treatment. These observations indicate that the anesthetic effects of phenobarbital potentiate with the TrkB stimulation and the resultant decrease in the cerebral KCC2 protein expression. The results also suggest that the TrkB protein and its phosphorylation status may be a key modulator of the pharmacological efficacy of phenobarbital.

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