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

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.

Keywords:

• Dalcetrapib
• JTT-705
• RO4607381
• pharmacokinetics
• covalent binding
• mixed disulfide
• CETP

Acknowledgments

The authors thank Hiroyuki Nemoto and Tomoyuki Noguchi of Sekisui Medical Co., Ltd (Tokyo, Japan) for pharmacokinetic study on dalcetrapib in monkeys and all members of the Drug Metabolism and Pharmacokinetics Research Laboratories of Japan Tobacco Inc. (Osaka, Japan) for the pharmacokinetic study on dalcetrapib in rats.

Disclosure statement

No potential conflict of interest was reported by the author(s).