title: SR-12813 lowers plasma cholesterol in beagle dogs by decreasing cholesterol biosynthesis.
abstract: SR-12813 inhibits cholesterol biosynthesis in Hep G2 cells via an enhanced degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Here we also show that SR-12813 inhibits cholesterol biosynthesis in vivo. A sterol balance study was performed in normolipemic beagle dogs. The dogs were given SR-12813 orally at dosages of 10 and 25 mg/kg/day for a period of 9 days. After 7 days plasma cholesterol was decreased by 15% in the 10 mg/kg/day group and by 19% in the 25 mg/kg/day group. Using a dual isotope technique no effects on intestinal cholesterol absorption were observed. The sterol balance indicated that endogenous synthesis of cholesterol was reduced by 23% in the 10 mg/kg/day group and by 37% in the 25 mg/kg/day group. Plasma lathosterol-cholesterol levels in dogs treated with 25 mg/kg/day SR-12813 were reduced by 56%, confirming a reduction of the cholesterol biosynthesis. Treatment with SR-12813 or the HMG-CoA reductase inhibitor lovastatin resulted in a large decrease in low density lipoprotein (LDL) cholesterol. It is concluded that SR-12813 reduces cholesterol biosynthesis in the dog model which results in a decrease of bile acid excretion, cholesterol excretion and plasma cholesterol level. The in vivo profile of SR-12813 is very similar to that of direct HMG-CoA reductase inhibitors, although the mode of action of the compound is unique.
authors.affiliation: Vascular Biology, SmithKline Beecham Pharmaceuticals, Harlow, Herts, UK. Theo_Berkhout_1@sbphrs.com
authors.forename: T A
authors.initials: TA
authors.lastname: Berkhout
authors.forename: H M
authors.initials: HM
authors.lastname: Simon
authors.forename: B
authors.initials: B
authors.lastname: Jackson
authors.forename: J
authors.initials: J
authors.lastname: Yates
authors.forename: N
authors.initials: N
authors.lastname: Pearce
authors.forename: P H
authors.initials: PH
authors.lastname: Groot
authors.forename: C
authors.initials: C
authors.lastname: Bentzen
authors.forename: E
authors.initials: E
authors.lastname: Niesor
authors.forename: W D
authors.initials: WD
authors.lastname: Kerns
authors.forename: K E
authors.initials: KE
authors.lastname: Suckling
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood*; D002791:Cholesterol, Dietary / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D008074:Lipoproteins / Q000097:blood / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D013261:Sterols / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D008078:Cholesterol, LDL; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D008074:Lipoproteins; C100355:SR 12813; D013261:Sterols; C001521:lathosterol; D002784:Cholesterol; D008148:Lovastatin