Dalcetrapib (JTT-705) is a cholesteryl ester transfer protein (CETP) inhibitor for rhCETP with an IC50 of 0.2 μM. Dalcetrapib modulates CETP activity. Dalcetrapib induces a conformational change in CETP, when added to human plasma. CETP-induced pre-β-HDL formation in human plasma is unchanged by Dalcetrapib ≤3 µM and increased at 10 µM. Dalcetrapib statistically and significantly increases pre-β-HDL formation.Dalcetrapib achieves 50% inhibition of CETP activity in human plasma at a concentration of 9 μM. Dalcetrapib inhibits the CETP activity of media in HepG2 in a dose-dependent manner. Treatment with Dalcetrapib results in significant increases in HDL-C levels. In hamsters injected with [3H]cholesterol-labeled autologous macrophages Dalcetrapib significantly increases fecal elimination of both [3H]neutral sterols and [3H]bile acids. Dalcetrapib increases plasma HDL-[3H]cholesterol.Dalcetrapib has 95% inhibition of CETP activity in male Japanese white rabbits at an oral dose of 30 mg/kg. Dalcetrapib increases the plasma HDL cholesterol level by 27% and 54%, respectively, when given at oral doses of 30 mg/kg or 100 mg/kg once a day for 3 days to male Japanese white rabbits.Treatment with Dalcetrapib markedly increases serum levels of HDL-C. The ratio of HDL2-C to HDL3-C is significantly higher in Dalcetrapib–treated rabbits than in control rabbits at 5 and 7 months, indicating that the inhibition of CETP activity by Dalcetrapib changes the distribution of HDL subfractions and preferentially increases HDL2-C levels. Dalcetrapib treatment increases serum paraoxonase activity and HDL-associated platelet-activating factor acetylhydrolase activity, but decreases the plasma lysophosphatidylcholine concentration. High-density lipoprotein cholesterol increases associated with co-administration of Dalcetrapib with ezetimibe (+29.8%) are comparable with those with Dalcetrapib alone (+25.6%), while the reduction in low-density lipoprotein cholesterol with co-administration (−35.9%) is greater than with ezetimibe alone (−20.9%). Dalcetrapib is generally well tolerated when administered alone and when co-administered with ezetimibe. The HDL-C increase with Dalcetrapib was not compromised by coadministration with statins, and reduction in low-density lipoprotein cholesterol with Dalcetrapib coadministered with statins was greater than with statins alone. Dalcetrapib alone and coadministered with statins was generally well tolerated. Dalcetrapib has enered in a phase III clinical trial in the treatment of cardiovascular disease, dyslipidemia, peripheral arterial disease (PAD).
||Seeding the HepG2 cells in 6-well plates and cultured to 70–80% confluence. After being washed with PBS, incubating the cells with growth medium and a different concentration (0 μM–30 μM) of chemical inhibitor Dalcetrapib and dissolving in 2% DMSO for 24 hours. Total RNA is used for RT-PCR.
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
|Body Surface Area (m2)
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by
||Animal B Km
|Animal A Km
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
||DMSO 70 mg/mL