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 ramipri lat were studied in conscious beagle dogs after sampling of cerebrospi nal fluid (CSF) and blood during chronic drug administration. The card iovascular effect of angiotensin-converting enzyme inhibitors have bee n suggested to be mediated partly by central action. Ramiprilat and ra mipril 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 rami prilat were measured in CSF over the 24-h period after both the 1 st a nd 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). Measur able concentrations of ramipril were recorded in plasma after oral dos ing (bioavailability approximately 45%), whereas in CSF the prodrug co ncentration was below the minimal determinable levels in most cases. I n 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 fo r ramiprilat were 8 ml/min/kg and 0.75 h. The CSF/plasma ratios for ra miprilat were essentially the same after i.v. administration of ramipr ilat and ramipril and, furthermore, the ratios did not differ signific antly from the ratios observed after oral administration of the prodru g. After i.v. dosing of ramipril the prodrug level was substantially h igher in CSF than in plasma. The CSF/plasma (unbound) ratios of ramipr il on day 7 were: 2.2 +/- 2.0 (2 h after dose), 10 +/- 7 (12 h after d ose) and 10 +/- 3 (24 h after dose). The prodrug ramipril was stable i n dog CSF (t 1/2 > 5 h). It is concluded that ramiprilat can penetrate the BBB as such, and that the conversion of ramipril to ramiprilat in side the blood-brain barrier seems to have little bearing on the ramip rilat levels in the CSF.