Pharmaceutical Society of Japan Acta Medica Okayama 0918-6158 48 1 2025 An Underlying Mechanism for the Altered Hypoglycemic Effects of Nateglinide in Rats with Acute Peripheral Inflammation 51 59 EN Haruka Toko Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Manami Ogino Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Akane Nishiwaki Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Moeko Kojina Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tetsuya Aiba Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The hypoglycemic effects of nateglinide (NTG) were examined in rats with acute peripheral inflammation (API) induced by carrageenan treatment, and the mechanisms accounting for altered hypoglycemic effects were investigated. NTG was administered through the femoral vein in control and API rats, and its plasma concentration profile was characterized. The time courses of the changes in plasma glucose and insulin levels were also examined. Although the plasma concentration profile of NTG in API rats was marginally distinguishable from that in control rats, the hypoglycemic effect of NTG was more persistent in API rats than in control rats. In addition, NTG elevated the plasma level of insulin more intensely in API rats than in control rats. Then, the islets of Langerhans were procured by perfusing the pancreas with collagenase solution in control and API rats, and the pancreatic mRNA expression of preproinsulin (Ins1), as well as that of sulfonylurea receptor ABCC8 (Abcc8), were examined. As a result, the expression of preproinsulin and ABCC8 mRNA increased in API rats. These findings suggest that the hypoglycemic effect of NTG was potentiated in API rats due to increased insulin secretion in the pancreas, which was caused by enhanced preproinsulin synthesis and expression of the sulfonylurea receptor. No potential conflict of interest relevant to this article was reported.

Pharmaceutical Society of Japan Acta Medica Okayama 0918-6158 44 1 2021 Acute Peripheral Inflammation Increases Plasma Concentration of Hypoglycemic Agent Nateglinide with Decreased Hepatic Drug-Metabolizing Activity in Rats 96 102 EN Moeko Kojina Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Keiichiro Suzuki Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Akane Nishiwaki Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tetsuya Aiba Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The effects of inflammation on hypoglycemic agents were evaluated in male rats with acute peripheral inflammation (API). Nateglinide (NTG) was utilized as a model compound, since it is a hepatically-metabolized compound and its metabolism is mainly mediated by CYP 2C11 enzyme. In the experiments, rats were subjected to carrageenan injection into their hind paws for API induction, and the plasma concentration profiles of NTG were then examined. In addition, pooled liver microsomes were prepared from control and API rats, and the hepatic drug-metabolizing activity toward NTG and the hepatic expression of CYP2C11 protein were evaluated. It was shown that the plasma concentration of NTG following its intravenous administration decreases at a slower rate in API rats than that in control rats. It was also indicated in the incubation study with the liver microsomes that the hepatic drug-metabolizing activity toward NTG decreases in API rats. Additionally, it was revealed in Western immunoblotting that the hepatic expression of CYP2C11 protein decreases in API rats. These findings suggest that inflammation occurring in peripheral tissues brings about a decrease in hepatic NTG metabolism by suppressing the hepatic expression of CYP2C11 protein, causing an alteration of the plasma concentration profile of NTG with its impaired elimination. No potential conflict of interest relevant to this article was reported.

Taylor & Francis Acta Medica Okayama 0049-8254 2019 Effects of dexamethasone to reverse decreased hepatic midazolam metabolism in rats with acute renal failure 1 9 EN Masami Doi Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Noriko Kajikawa Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tetsuya Aiba Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The inductive effects of dexamethasone on hepatic midazolam metabolism were examined in Wistar rats with acute renal failure (ARF) to clarify whether the ARF-related decrease in the hepatic expression of drug-metabolizing enzymes is caused by an impairment in the translation/polypeptide formation process. ARF was induced with intramuscular glycerol injection. Dexamethasone was orally administered. Pooled liver microsomes from five rats were prepared with ultracentrifugation for each of four groups, namely, control and ARF rats, control rats with dexamethasone treatment and ARF rats with dexamethasone treatment. Hepatic drug-metabolizing activity was examined in an incubation study with the microsomes, where midazolam was employed as a substrate of cytochrome P450 (CYP) 3A enzymes. The hepatic protein and mRNA expressions of CYP3A23/3A1 and 3A2 enzymes were also evaluated. With dexamethasone treatment, the hepatic metabolic rate of midazolam increased 1.4 times in control rats, while it increased 19.6 times in ARF rats, reflecting the greater induction of hepatic protein expressions of CYP3A enzymes in ARF rats than in control rats. The hepatic protein expression process for CYP3A23/3A1 and 3A2 responds well to dexamethasone treatment in ARF rats, indicating that the translation/polypeptide formation process is not impaired in the presence of ARF. No potential conflict of interest relevant to this article was reported.

日本静脈経腸栄養学会 Acta Medica Okayama 1344-4980 29 4 2014 粉砕法による経管投与における薬剤量損失に対する簡易懸濁法の有用性についての検討 1027 1033 EN Yoshito Zamami Toshihiro Koyama Tetsuya Aiba Manabu Amano Tetsuaki Ando Naomi Kurata Hideki Nawa Hironori Nakura Yoshihisa Kitamura Toshiaki Sendo 【目的】従来の薬剤経管投与法である粉砕法は薬効の減少につながる薬剤量の損失が指摘されている。そこで粉砕法による薬剤量損失に対する簡易懸濁法の有用性について検討した。 【方法】頻繁に粉砕指示がなされる5種類の薬剤を用いて粉砕・分包による薬物含量減少、薬剤調製時の懸濁性および実際の経管投与を想定した薬物含量について2つの方法を比較した。 【結果】薬剤を粉砕・分包するとそれぞれの薬物含量は減少した。またワーファリン®錠を粉砕して水に溶解すると完全には懸濁せず、小さな塊が生じたが、簡易懸濁法では均一に懸濁した。ワーファリン®錠の経管投与を想定した実験において粉砕法では薬物含量が大幅に減少したが、簡易懸濁法では、ほとんど損失が認められなかった。【結論】簡易懸濁法は粉砕法に比べて薬剤損失の面で有用性が高いことが示唆され、ワーファリン®錠のように安定性が悪い薬剤では特に適正な薬物投与に貢献出来ると考えられる。 No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 343 2008 Evaluation of intramuscular lateral distribution profile of topically administered acetaminophen in rats EN Yuji Kurosaki Masahiro Tagawa Akiho Omoto Hiroshi Suito Yukiko Komori Hiromu Kawasaki Tetsuya Aiba <p>&#65279;To clarify to what extent topically administered drug molecules horizontally permeate into tissues surrounding the administration site, the intramuscular lateral concentration profile of acetaminophen was investigated in vivo using the microdialysis method in rats. When acetaminophen was intramuscularly administered for 6 hr in a pinpoint manner at a constant rate of 3 &#956;g/min, it was clearly detected in the muscle surrounding the administration site, being 17.5 &#956;g/ml when measured at a 2 mm distance from the administration site. The concentration in the muscle was decreased as the distance increased, and those measured at 5 mm and 40 mm were 0.35 &#956;g/ml and 0.09 &#956;g/ml, respectively. In addition, it was shown that the concentration in the muscle at 40 mm reflected the compound’s concentration in plasma, but not the compound’s horizontal permeation from the administration site. With these observations, the intramuscular distribution profile of acetaminophen was numerically characterized according to Fick’s law. As a result, it was revealed that horizontal permeation is the primary process accountable for the increased intramuscular concentration only in the area adjacent to the administration site, and the radius of the adjacent area was calculated to be 5.80 mm for acetaminophen. </p> No potential conflict of interest relevant to this article was reported.