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)