Takubo Hiroaki, Ishikawa Tomohiro, Taniguchi Toshio, Iwanaga Kazunori, Nomura Yukihiro
Drug Metabolism and Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Osaka, Japan.
Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Osaka, Japan.
Xenobiotica. 2021 Jan;51(1):82-87. doi: 10.1080/00498254.2020.1809030. Epub 2020 Aug 20.
We investigated the influence of multiple oral administration on the accumulation of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, in rats. It is well known that orally administered dalcetrapib is rapidly hydrolysed to its active form, which has a sulfhydryl group, in the body. The active form then binds covalently to endogenous thiols via mixed disulfide bonds. Following multiple once daily oral administration of C-dalcetrapib for seven days to rats, the concentration of radioactivity in the plasma and almost all tissues reached the steady state by day 4. At 24 h after the last dose, there was a relatively high concentration of radioactivity in the mesenteric lymph nodes, liver, adrenal glands and fat. After the last dose to rats, the radioactivity was almost completely recovered in the urine and faeces, indicating that dalcetrapib is not retained in the body, probably due to the reversibility of the disulfide bonds despite being covalent bonds.
我们研究了多次口服给药对新型胆固醇酯转移蛋白抑制剂达塞曲匹（JTT-705/RO4607381）在大鼠体内蓄积的影响。众所周知，口服的达塞曲匹在体内会迅速水解为其具有巯基的活性形式。然后，活性形式通过混合二硫键与内源性硫醇共价结合。对大鼠每日一次多次口服C-达塞曲匹，持续7天，到第4天时，血浆和几乎所有组织中的放射性浓度均达到稳态。在最后一剂给药24小时后，肠系膜淋巴结、肝脏、肾上腺和脂肪中的放射性浓度相对较高。对大鼠最后一剂给药后，尿液和粪便中几乎完全回收了放射性，这表明达塞曲匹不会在体内蓄积，这可能是由于尽管二硫键是共价键，但具有可逆性。
