The mechanism of comparable serum cholesterol lowering effects of pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, between once- and twice-daily treatment regimens in beagle dogs and rabbits.
In dogs, no significant difference in the reduction of serum cholesterol was observed among three dosing regimens of pravastatin: once in the 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 were 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 (LDL) receptor protein was increased 1.2-1.3-fold (P < 0.05) by both treatments, and no significant difference was noted between these treatment regimens. In addition, there was no significant difference in the extent of up-regulated LDL receptor protein between once-daily dosing in the evening and once-daily dosing in the morning. In the experiments with rabbit hepatocytes, the up-regulated LDL receptor activity induced by preincubation with pravastatin was retained even 24 hr after the removal of pravastatin. These results suggest that the comparable efficacy of pravastatin between once- and twice-daily treatment could be explained by retention of up-regulated LDL receptor activity for more than 24 hr in vitro and in vivo.
Fujioka
T
T
Pharmacology Research Laboratory, Sankyo Co., Ltd., Tokyo, Japan.
Nara
F
F
Shimada
Y
Y
Fukushige
J
J
Shimotsu
H
H
Shigehara
E
E
Fukami
M
M
Tsujita
Y
Y
D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001667:Binding, Competitive; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015151:Immunoblotting; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D013045:Species Specificity; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007457:Iodine Radioisotopes; D011973:Receptors, LDL; D002784:Cholesterol; D017035:Pravastatin