The influence of multiple oral administration on the pharmacokinetics and distribution profile of dalcetrapib in rats.

Hiroaki Takubo, Tomohiro Ishikawa, Toshio Taniguchi, Kazunori Iwanaga, Yukihiro Nomura

Xenobiotica; the fate of foreign compounds in biological systems 2021 Jan

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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 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. 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.

Citation

Hiroaki Takubo, Tomohiro Ishikawa, Toshio Taniguchi, Kazunori Iwanaga, Yukihiro Nomura. The influence of multiple oral administration on the pharmacokinetics and distribution profile of dalcetrapib in rats. Xenobiotica; the fate of foreign compounds in biological systems. 2021 Jan;51(1):82-87