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

Abstract

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)methyl]phenyl]-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.

• Authors: M Shiomi, T Ito
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 431 Issue 1 Pg. 127-31 (Nov 09 2001) ISSN: 0014-2999 [Print] Netherlands
• PMID: 11716851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cholesterol, LDL
• Indoles
• Lipoproteins, VLDL
• Pyridines
• Receptors, LDL
• Triglycerides
• microsomal triglyceride transfer protein
• Vitamin E
• Cholesterol
• implitapide

Topics

• Animals
• Carrier Proteins (antagonists & inhibitors)
• Cholesterol (blood)
• Cholesterol, LDL (blood)
• Disease Models, Animal
• Down-Regulation
• Hyperlipoproteinemia Type II (blood, drug therapy)
• Indoles (pharmacology, therapeutic use)
• Lipoproteins, VLDL (blood)
• Liver (drug effects, metabolism)
• Pyridines (pharmacology, therapeutic use)
• Rabbits
• Receptors, LDL (blood, deficiency)
• Triglycerides (blood)
• Vitamin E (blood)