Action of the new hypolipidemic agent lifibrol (K12.148) on lipid homeostasis in normal rats: plasma lipids, hepatic sterologenesis, and the fate of injected [14C]acetate.
Lifibrol, a new hypocholesterolemic agent with activity in humans, was examined in normal rats for its short-term and long-term effects on lipid homeostasis. Cholesterol (Chol) synthesis inhibition by lifibrol was demonstrated in vitro in liver minces from normal rats by following [1-14C]acetate ([14C]Ac) and DL-[2-14C]mevalonate ([14C]-MVA) incorporation into [14C]Chol. When administered at 50 mg/kg/d, lifibrol reduced plasma total Chol and triglycerides (TG) (P < 0.001) within 24 h. The Chol reduction was largely a result of reduction of low density and very low density lipoprotein cholesterol (LDL + VLDL-chol) and a smaller decrease in high density lipoprotein cholesterol (HDL-chol). After 10 d, however, a rebound effect emerged, and after 41 d, plasma Chol, LDL + VLDL-chol, and HDL-chol were restored. In contrast, plasma TG remained at reduced levels (P < 0.01). The rebound is attributed to counter-regulation of hepatic sterologenesis that was assessed both ex vivo and in vivo. The ex vivo incorporation of [14C]MVA and [14C]octanoate into [14C]Chol and total digitonin-precipitable [14C]sterols ([14C]DPS) in liver minces was increased 2-and 6-fold, respectively, in rats treated 6 d at 50 mg/kg. Similarly, in vivo incorporation of intraperitoneally injected [14C]Ac into hepatic [14C]DPS (2 h post-injection) was increased 2- to 5-fold at 50 mg/kg, and evidence for increased sterologenesis in nonhepatic tissue was also obtained. The increased hepatic sterologenesis, evident within 48 h, persisted out to 41 d of treatment by which time increases (P < 0.002) in hepatic Chol and carcass total sterols were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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Upjohn Laboratories, Kalamazoo, Michigan 49001.
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D000085:Acetates / Q000493:pharmacokinetics; D000818:Animals; D000440:Butanols / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D062385:Hydroxybenzoates / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013261:Sterols / Q000096:biosynthesis
D000085:Acetates; D000440:Butanols; D062385:Hydroxybenzoates; D000960:Hypolipidemic Agents; D008055:Lipids; D013261:Sterols; C059343:lifibrol