IN-VIVO AND IN-VITRO BLOOD-BRAIN-BARRIER TRANSPORT OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A (HMG-COA) REDUCTASE INHIBITORS

Among the HMG-CoA reductase inhibitors, lovastatin and simvastatin hav e central nervous system (CNS) side effects, such as sleep disturbance , whereas pravastatin does not. This difference in CNS side effects ma y be due to a difference in blood-brain barrier (BBB) permeability amo ng these inhibitors. To test this hypothesis, we compared the BBB tran sport ability of HMG-CoA reductase inhibitors by using an in vivo brai n perfusion technique in rats and an in vitro culture system of bovine brain capillary endothelial cells. The in vivo BBB permeability coeff icients of the lipophilic inhibitors, [C-14]lovastatin and [C-14]simva statin, were high. In contrast, that of the hydrophilic inhibitor, [C- 14]pravastatin, was low and not significantly different from that of [ C-14]sucrose, an extracellular space marker. Similarly, the in vitro B BB permeability coefficients of [C-14]lovastatin and [C-1]simvastatin were high, while that of [C-14]pravastatin was low. The in vivo and in vitro transcellular permeabilities obtained for HMG-CoA reductase inh ibitors were comparable. This study shows that the BBB permeability co rrelates with the CNS side effects of the HMG-CoA reductase inhibitors .