THE MECHANISM OF COMPARABLE SERUM-CHOLESTEROL LOWERING EFFECTS OF PRAVASTATIN SODIUM, A 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A INHIBITOR, BETWEEN ONCE-DAILY AND TWICE-DAILY TREATMENT REGIMENS IN BEAGLE DOGS ANDRABBITS

In dogs, no significant difference in the reduction of serum cholester ol was observed among three dosing regimens of pravastatin: once in th e morning (3 mg/kg), once in the evening (3 mg/kg), and twice-daily (1 .5 mg/kg x 2) for 21 days. In rabbits, pravastatin was administered at a dose of 50 mg/kg once-daily given in the evening or 25 mg/kg twice- daily for 14 days; the respective serum and liver cholesterol levels w ere decreased by 41% and 7% in the once-daily dosing and by 51% and 11 % in the twice-daily dosing. The amount of low density lipoprotein (LD L) receptor protein was increased 1.2-1.3-fold (P<0.05) by both treatm ents, and no significant difference was noted between these treatment regimens. In addition, there was no significant difference in the exte nt of up-regulated LDL receptor protein between once-daily dosing in t he evening and once-daily dosing in the morning. In the experiments wi th rabbit hepatocytes, the up-regulated LDL receptor activity induced by preincubation with pravastatin was retained even 24 hr after the re moval of pravastatin. These results suggest that the comparable effica cy of pravastatin between once- and twice-daily treatment could be exp lained by retention of up-regulated LDL receptor activity for more tha n 24 hr in vitro and in vivo.