Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG-CoA reductase inhibitors.
Hepatic specificity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may be achieved by efficient first-pass liver extraction resulting in low circulating drug levels, as with lovastatin, or by lower cellular uptake in peripheral tissues, seen with pravastatin. BMY-21950 and its lactone form BMY-22089, new synthetic inhibitors of HMG-CoA reductase, were compared with the major reference agent lovastatin and with the synthetic inhibitor fluindostatin in several in vitro and in vivo models of potency and tissue selectivity. The kinetic mechanism and the potency of BMY-21950 as a competitive inhibitor of isolated HMG-CoA reductase were comparable to the reference agents. The inhibitory potency (cholesterol synthesis assayed by 3H2O or [14C]acetate incorporation) of BMY-21950 in rat hepatocytes (IC50 = 21 nM) and dog liver slices (IC50 = 23 nM) equalled or exceeded the potencies of the reference agents. Hepatic cholesterol synthesis in vivo in rats was effectively inhibited by BMY-21950 and its lactone form BMY-22089 (ED50 = 0.1 mg/kg p.o.), but oral doses (20 mg/kg) that suppressed liver synthesis by 83-95% inhibited sterol synthesis by only 17-24% in the ileum. In contrast, equivalent doses of lovastatin markedly inhibited cholesterol synthesis in both organs. In tissue slices from rat ileum, cell dispersions from testes, adrenal, and spleen, and in bovine ocular lens epithelial cells, BMY-21950 inhibited sterol synthesis weakly in vitro with IC50 values 76- and 188-times higher than in hepatocytes; similar effects were seen for BMY-22089. However, the IC50 ratios (tissue/hepatocyte) for lovastatin and fluindostatin were near unity in these models. Thus, BMY-21950 and BMY-22089 are the first potent synthetic HMG-CoA reductase inhibitors that possess a very high degree of liver selectivity based upon differential inhibition sensitivities in tissues. This cellular uptake-based property of hepatic specificity of BMY-21950 and BMY-22089, also manifest in pravastatin, is biochemically distinct from the pharmacodynamic-based disposition of lovastatin, which along with fluindostatin exhibited potent inhibition in all tissues that were exposed to it.
Bristol-Myers Squibb Co., Department of Cardiovascular Research, Wallingford, CT 06492.
R A
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Parker
R W
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Clark
S Y
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Sit
T L
TL
Lanier
R A
RA
Grosso
J J
JJ
Wright
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology*; D002417:Cattle; D002784:Cholesterol / Q000096:biosynthesis*; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007082:Ileum / Q000201:enzymology / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D007908:Lens, Crystalline / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D011714:Pyrans / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013777:Tetrazoles / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D001393:Azoles; D002070:Butadienes; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011714:Pyrans; D011753:Pyrones; D013777:Tetrazoles; C060957:BMY 22089; C065178:BMY 21950; D000077340:Fluvastatin; D002784:Cholesterol; D008148:Lovastatin