Quantification of Hydrochlorothiazide and Ramipril/Ramiprilate in Blood Serum and Cerebrospinal Fluid: A Pharmacokinetic Assessment of Central Nervous System Adverse Effects.

BACKGROUND: A drug must reach the central nervous system (CNS) in order to directly cause CNS adverse effects (AEs). Our current study addressed the pharmacokinetic (PK) background of the assumption that CNS concentrations of hydrochlorothiazide (HCT) and ramiprilate may directly cause CNS AEs such as headache and drowsiness. METHODS: In neurological patients, paired serum and cerebrospinal fluid (CSF) samples were withdrawn simultaneously. Some of them were treated with HCT (n = 15, daily chronic doses 7.5-25 mg) or ramipril (n = 9, 2.5-10 mg). Total concentrations of HCT and ramiprilate were quantified in these samples. To this end, sensitive liquid chromatography/tandem mass spectrometry methods were developed. RESULTS: CSF reached 4.1% (interquartile ranges 2.5-5%) of total serum concentrations for HCT and 2.3% (1.7-5.7%) for ramiprilate, corresponding to about 11.3% and 5.5% of respective unbound serum concentrations. CONCLUSION: The PK/Pharmacodynamic characteristics of HCT and ramiprilate in the CNS are unknown. However, since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, it is unlikely that the observed CNS AEs are mediated primarily via direct effects in the brain.

Central nervous and systemic kinetics of ramipril and ramiprilat in the conscious dog.

The central nervous and systemic kinetics of ramipril, an angiotensin-converting enzyme inhibitor prodrug, and its active metabolite ramiprilat were studied in conscious beagle dogs after sampling of cerebrospinal fluid (CSF) and blood during chronic drug administration. The cardiovascular effect of angiotensin-converting enzyme inhibitors have been suggested to be mediated partly by central action. Ramiprilat and ramipril were determined in CSF and plasma by a gas chromatographic-mass spectrometric assay method. After 10 mg/kg of ramipril, given orally to four dogs once daily for 7 days, significant concentrations of ramiprilat were measured in CSF over the 24-h period after both the 1st and 7th day of treatment. The CSF/plasma (unbound) ratios of ramiprilat on day 7 were (mean +/- S.D.): 0.01 +/- 0.003 (2 h after dose), 0.18 +/- 0.05 (12 h after dose) and 0.32 +/- 0.11 (24 h after dose). Measurable concentrations of ramipril were recorded in plasma after oral dosing (bioavailability approximately 45%), whereas in CSF the prodrug concentration was below the minimal determinable levels in most cases. In a second set of experiments, ramiprilat (3 mg/kg) or ramipril (3 mg/kg) were given i.v. to three dogs once daily for 7 days. Ramipril was rapidly cleared from the plasma, clearance being approximately 140 ml/min/kg and half-life about 0.5 h on day 7. The corresponding values for ramiprilat were 8 ml/min/kg and 0.75 h. The CSF/plasma ratios for ramiprilat were essentially the same after i.v. administration of ramiprilat and ramipril and, furthermore, the ratios did not differ significantly from the ratios observed after oral administration of the prodrug.(ABSTRACT TRUNCATED AT 250 WORDS)