HEPATIC RESPONSES TO INHIBITION OF 3-HYDROXY-3-METHYLGLUTARYL-COA-REDUCTASE - A COMPARISON OF ATORVASTATIN AND SIMVASTATIN

We have compared the cellular responses to simvastatin (Simva) and ato rvastatin (Atorva), two potent HMG-CoA reductase inhibitors. The two d rugs exhibited similar IC50's for inhibition of either rat or human re ductase, and single oral dosing in rats showed the compounds to be nea rly equipotent at inhibiting hepatic cholesterol synthesis. Treatment of rats with Simva or Atorva in the feed for four days yielded compara ble inductions of hepatic reductase activity and reductase protein. Fo r example, 0.05% Simva induced reductase activity 27.3 +/- 9.1 fold an d 0.05% Atorva induced activity 26.9 +/- 4.7 fold. This adaptive respo nse was also studied in HepG2 cells, a human hepatoblastoma line, cult ured for 24 h in delipidated serum and then for an additional 24 h wit h Simva or Atorva. Over a broad range (10 nM-10 mu M), both drugs caus ed similar inductions of reductase activity, reductase protein, and re ductase mRNA. Under all conditions, the drugs induced similar changes in the ratio of mRNA/protein suggesting that Simva and Atorva have sim ilar effects on both transcriptional and post-transcriptional regulato ry machinery. Moreover, reductase in cells treated with Simva or Atorv a for 22 h responded similarly to subsequent challenge with 25-hydroxy cholesterol. Finally, we measured the ability of the two reductase inh ibitors to reduce ApoB secretion by HepG2 cells. Simva and Atorva at 0 .5 mu M inhibited ApoB secretion nearly identically, 38% and 42% respe ctively. We conclude that these two drugs induce similar adaptive resp onses in cells and that their actions are qualitatively and mechanisti cally identical. Human studies have shown that plasma is cleared of At orva much more slowly than it is of Simva. The large pharmacokinetic d ifference in man, rather than some difference in mechanism, is the mos t likely explanation for the finding that the equipotent dose ratio fo r cholesterol lowering in humans of Simva to Atorva is about 2/1. (C) 1998 Elsevier Science B.V.