Effect of Chronic Hypertension on the Blood–Brain Barrier Permeability of Libenzapril

Very little information is available on the permeability of theblood–brain barrier (BBB) to small polar drugs inchronic hypertension. The blood and cerebrospinal fluid (CSF)pharmacokinetics of liben-zapril (LZP), a potentangiotensin converting enzyme inhibitor, were investigated inhypertensive (SH) and normotensive (SD) rats.Following intravenous bolus administration of this hydrophilic drug, theterminal rate constant for elimination (β),steady-state volume of distribution (\(V_{d_{ss} }\)), and systemic clearance (CL) were similar in these two animalgroups. Other pharmacokinetic parameters (C_p°,α, k_l2, and k₂₁)were significantly (P < 0.05) greater in thehypertensive 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 ofarea under the concentration–time curve (AUC) in CSF toblood was about twofold higher in SH rats compared to normotensive rats,showing increased BBB permeability in hypertensive rats. An acute brainuptake study was also performed in SH, SD, and WK rats by intracarotidadministration of ¹⁴C-LZP along with³H₂O as a reference marker. Both LZP and watertransport was found to be significantly higher (about two-to five-fold) in six of the seven different brain regions inSH rats as compared to the normotensive (SD and WK) controls.Because of this simultaneous increase in concentrations of both the drugand the reference marker, BUI values were not affected. Regional brainconcentrations in SH rats were also linearly correlated with the meanarterial pressure (MAP) values, providing further evidence ofthe systemic pressure related increase in BBB permeability.