EFFECT OF CHRONIC HYPERTENSION ON THE BLOOD-BRAIN-BARRIER PERMEABILITY OF LIBENZAPRIL

Very little information is available on the permeability of the blood-brain barrier (BBB) to small polar drugs in chronic hypertension. The blood and cerebrospinal fluid (CSF) pharmacokinetics of libenzapril (LZP), a potent angiotensin converting enzyme inhibitor, were investigated in hypertensive (SH) and normotensive (SD) rats. Following intravenous bolus administration of this hydrophilic drug, the terminal rate constant for elimination (beta), steady-state volume of distribution (V(d(ss))), and systemic clearance (CL) were similar in these two animal groups. Other pharmacokinetic parameters (C(p)o, alpha, k12, and k21) were significantly (P < 0.05) greater in the hypertensive group, except for the volume of the central compartment (V(c)) and ratio of V(c) to V(d(ss)), which were smaller in SH rats. The ratio of area under the concentration-time curve (AUC) in CSF to blood was about twofold higher in SH rats compared to normotensive rats, showing increased BBB permeability in hypertensive rats. An acute brain uptake study was also performed in SH, SD, and WK rats by intracarotid administration of C-14-LZP along with (H2O)-H-3 as a reference marker. Both LZP and water transport was found to be significantly higher (about two- to five-fold) in six of the seven different brain regions in SH rats as compared to the normotensive (SD and WK) controls. Because of this simultaneous increase in concentrations of both the drug and the reference marker, BUI values were not affected. Regional brain concentrations in SH rats were also linearly correlated with the mean arterial pressure (MAP) values, providing further evidence of the systemic pressure related increase in BBB permeability.