MTP inhibitor decreases plasma cholesterol levels in LDL receptor-deficient WHHL rabbits by lowering the VLDL secretion

To examine whether a microsomal triglyceride transfer protein (MTP)-inhibitor is effective in patients with homozygous familial hypercholesterolemia, we administered (2S)-2-cyclopentyl-2-{4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyllphenyl}-N-[(1S)-2-hydroxy-1-phenylethyl]ethanamide (Implitapide), a new MTP inhibitor, to low-density lipoprotein (LDL)-receptor-deficient Watanabe heritable hyperlipidemic (WHHL) rabbits at doses of 3, 6, and 12 mg/kg for 4 weeks. In the 12 mg/kg group, the plasma cholesterol and triglyceride levels were decreased by 70% and 45%, respectively, and the very low-density lipoprotein (VLDL) secretion rate was decreased by 80%. The composition of newly secreted VLDL was similar in each group. This suggests that Implitapide diminished the number of VLDL particles secreted from the liver. Although the ratio of vitamin E/LDL was not altered by Implitapide, triglyceride accumulation and a decrease in vitamin E were observed in the liver. In conclusion, an inhibition of VLDL secretion led to a decrease of plasma LDL in WHHL rabbits, and MTP inhibitors should have hypolipidemic effects against homozygous familial hypercholesterolemia. (C) 2001 Elsevier Science BN. All rights reserved.