SR-12813 lowers plasma cholesterol in beagle dogs by decreasing cholesterol biosynthesis.
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.
Berkhout
T A
TA
Vascular Biology, SmithKline Beecham Pharmaceuticals, Harlow, Herts, UK. Theo_Berkhout_1@sbphrs.com
Simon
H M
HM
Jackson
B
B
Yates
J
J
Pearce
N
N
Groot
P H
PH
Bentzen
C
C
Niesor
E
E
Kerns
W D
WD
Suckling
K E
KE
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
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