Comparison between morning and evening single dose administration of simvastatin on endothelium-dependent relaxation and superoxide dismutase enzyme level as an antioxident marker in cholesterol-fed rabbits

ABSTRACT

Statins are widely used hypocholesterolemic drugs that act through reversible competitive inhibition of the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase [HMGCOA] enzyme. At first, morning use of statins was recommended but now it is known that choesterogenesis follows a circadian rhythm as it occurs at a higher rate during the evening time. Accordingly, accurate timing of statin administration should be re-evaluated in order to obtain the best therapeutic effect. As simvastatin is one of the widely prescribed HMG-CoA reductase inhibitors, it was chosen in this study to test and compare its effectiveness when administered as single dose in the morning and in the evening. The experiments were performed on Newzealand rabbits divided into four equal groups, each composed of 8 animals control normocholesterolemic, hypercholesterolemic nontreated, hypercholesterolemic treated with morning simvastatin, and hypercholesterolemic treated with evening simvastatin. Animals of control group received a cholesterol-free diet for 16 weeks, while animals of the other three groups were maintained on a high cholesterol diet for an equal duration of time. Treated groups received simvastatin in a single oral daily dose of 10 mg/kg for 8 weeks starting at the beginning of the 9[th] week, administered either in the morning or in the evening. Blood cholesterol level was checked for all animals at the end of the 4[th], 8[th], l2[th] and 16[th] weeks. At the end of the 16[th] week, the level of the anti-oxidant superoxide dismutase [SOD] enzyme was determined in erythrocyte [RBC] lysates obtained from animals of all groups. The animals were then slaughtered and vascular reactivity to acetvlcholine [ACh] was tested on ring preparations obtained from their isolated aortae [ring preparations]. Both morning and evening treatment with simvastatin significantly reduced blood cholesterol level, augmented relaxation induced by [ACh] and increased SOD level in RBCs lysates, in comparison with non-treated hypercholestero!emic group. However, results obtained with the evening dosing regimen were much more significant when compared with the morning dosing schedule. It is concluded that therapeutic efficiency of simvastatin is best obtained when the drug is administered in the evening rather than in the morning. This most likely occurs due to the circadian rhythm of cholesterol biosynthesis that tends to occur at a much greater rate during night as a result of increased availability of cholesterol precursors. This chronotherapeutic pattern of simvastatin recommends its night administration to ensure introduction of the drug at the correct timing thus achieving the best therapeutic effect