Biological Activity
torcetrapib is a cetp inhibitor with ic50 of 37 nm, elevates hdl-c and reduces nonhdl-c in plasma. inhibition of cholesteryl ester transfer protein (cetp) has been shown to have a substantial effect on plasma lipoprotein levels.
in vitro
torcetrapib dose-dependently increases aldosterone release from h295r cells after either 24 or 48 h of treatment, this effect is mediated by calcium channel as calcium channel blockers completely blocks torcetrapib-induced corticoid release and calcium increase. torcetrapib (1 μm) significantly increases the expression of steroidogenic gene, cyp11b2 and cyp11b1, in h295r cell lines [1].
in vivo
researchers tested torcetrapib in rabbits fed an atherogenic diet at a dose sufficient to increase hdl-c by at least 3-fold. cetp activity was inhibited by 70–80% throughout the study. non-hdl-c increased in both groups, but there was no difference apparent by the study’s end [2].
References
[1] hu x, dietz jd, xia c, knight dr, loging wt, smith ah, yuan h, perry da, keiser j. torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. endocrinology. 2009;150(5):2211-9.
[2] morehouse la, sugarman ed, bourassa pa, sand tm, zimetti f, gao f, rothblat gh, milici aj. inhibition of cetp activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in new zealand white rabbits. j lipid res. 2007;48(6):1263-72.
[3] barter pj, caulfield m, eriksson m, grundy sm, kastelein jj, komajda m, lopez-sendon j, mosca l, tardif jc, waters dd, shear cl, revkin jh, buhr ka, fisher mr, tall ar, brewer b; illuminate investigators. effects of torcetrapib in patients at high risk for coronary events. n engl j med. 2007;357(21):2109-22.
