ISSN:
1573-904X
Keywords:
blood–brain barrier (BBB)
;
pharmacokinetics
;
liben-zapril
;
cerebrospinal fluid (CSF)
;
chronic hypertension
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract 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 (Cp°,α, k l2, and k 21)were significantly (P 〈 0.05) greater in thehypertensive group, except for the volume of the central compartment(Vc) and ratio of Vc 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1018945608888
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