Abstract

1. 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.

2. 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.

3. Following multiple once daily oral administration of ¹⁴C-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.

4. 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.

摘要

1. 我们研究了多次口服对大鼠中新的胆固醇酯转移蛋白抑制剂dalcetrapib（JTT-705 / RO4607381）积累的影响。

2. 众所周知，口服达塞曲匹在体内迅速水解成其具有巯基的活性形式。然后，活性形式通过混合的二硫键与内源硫醇共价结合。

3. 每天多次向大鼠口服一次¹⁴ C-dalcetrapib，连续7天后，到第4天血浆和几乎所有组织中的放射性浓度达到稳定状态。在最后一次给药后24小时，浓度相对较高肠系膜淋巴结，肝脏，肾上腺和脂肪的放射性

4. 在给大鼠最后一剂后，放射性几乎在尿液和粪便中完全恢复，这表明达达曲非没有保留在体内，这可能是由于尽管是共价键，但二硫键可逆。