MULTIPLE-DOSE PHARMACOKINETICS OF RAMIPRIL IN PATIENTS WITH CHRONIC CONGESTIVE-HEART-FAILURE

Thirteen patients with chronic congestive heart failure of NYHA class II-III received multiple doses (14 days) of ramipril (5 mg once daily) ; the concentrations of ramipril and ramiprilat in plasma, as well as ramipril, ramiprilat, glucuronides, diketopiperazine, and diketopipera zine acid in urine were measured at various times for 14 days. One pat ient dropped out after the first day due to hypotension and another wh o accidentally received another ACE inhibitor additionally was exclude d, so that 11 patients completed the study. Ramipril and ramiprilat in plasma were determined by radioimmunoassay, and ramipril and its meta bolites in urine were measured by gas chromatography in the laboratori es of Hoechst AG. Peak concentrations of the active substance ramipril at were reached after about 4 h and amounted to 22.3 +/- 11.1 ng/ml af ter the first dose, and a peak concentration of 26.6 +/- 10.0 ng/ml wa s observed 2.5 +/- 1.4 h on average after administration on day 14. Pr actically no accumulation was observed for ramiprilat; the AUD (0-24 h ) values increased from 191.3 +/- 83.1 ng h/ml for the first study day to 238.3 +/- 98.0 ng h/ml for day 14. As expected, only very small fr actions of the dose were excreted with urine as unchanged ramipril and ramipril glucuronide. Ramiprilat is excreted with urine to a larger e xtent than is rampiril-on average 6.6 +/- 3.0% on the first day and 12 .2 +/- 3.8% on day 14. The total amount excreted increased by 34% on a verage, and was mainly due to an increased ramiprilat excretion. The m aximum inhibition of angiotensin-converting enzyme was practically ide ntical for days 1 and day 14, that is, 99.5 +/- 1.0% and 99.2 +/- 1.2% , respectively. Because of the residual ramiprilat concentration at da y 14, the maximum inhibition was reached earlier on day 14 (3.6 +/- 2. 7 h) than on day 1 (4.2 +/- 2.3 h).