Hepatic and nonhepatic sterol synthesis and tissue distribution following administration of a liver selective HMG-CoA reductase inhibitor, CI-981: comparison with selected HMG-CoA reductase inhibitors.
Since cholesterol biosynthesis is an integral part of cellular metabolism, several HMG-CoA reductase inhibitors were systematically analyzed in in vitro, ex vivo and in vivo sterol synthesis assays using [14C]acetate incorporation into digitonin precipitable sterols as a marker of cholesterol synthesis. Tissue distribution of radiolabeled CI-981 and lovastatin was also performed. In vitro, CI-981 and PD134967-15 were equipotent in liver, spleen, testis and adrenal, lovastatin was more potent in extrahepatic tissues than liver and BMY21950, pravastatin and PD135023-15 were more potent in liver than peripheral tissues. In ex vivo assays, all inhibitors except lovastatin preferentially inhibited liver sterol synthesis; however, pravastatin and BMY22089 were strikingly less potent in the liver. CI-981 inhibited sterol synthesis in vivo in the liver, spleen and adrenal while not affecting the testis, kidney, muscle and brain. Lovastatin inhibited sterol synthesis to a greater extent than CI-981 in the spleen, adrenal and kidney while pravastatin and BMY22089 primarily affected liver and kidney. The tissue distribution of radiolabeled CI-981 and lovastatin support the changes observed in tissue sterol synthesis. Thus, we conclude that a spectrum of liver selective HMG-CoA reductase inhibitors exist and that categorizing agents as liver selective is highly dependent upon method of analysis.
Bocan
T M
TM
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Ferguson
E
E
McNally
W
W
Uhlendorf
P D
PD
Bak Mueller
S
S
Dehart
P
P
Sliskovic
D R
DR
Roth
B D
BD
Krause
B R
BR
Newton
R S
RS
D000818:Animals; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics*; D000069059:Atorvastatin; D005231:Fatty Acids, Unsaturated / Q000493:pharmacokinetics; D006538:Heptanoic Acids / Q000493:pharmacokinetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008148:Lovastatin / Q000493:pharmacokinetics; D008297:Male; D017035:Pravastatin / Q000493:pharmacokinetics; D011758:Pyrroles / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013261:Sterols / Q000096:biosynthesis*; D013777:Tetrazoles / Q000493:pharmacokinetics; D014018:Tissue Distribution
D000924:Anticholesteremic Agents; D005231:Fatty Acids, Unsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D013261:Sterols; D013777:Tetrazoles; C065178:BMY 21950; D008148:Lovastatin; D000069059:Atorvastatin; D017035:Pravastatin