RESUMO
Four cholecystectomy patients, aged between 52 and 56 years, weighing between 64 and 90 kg, received 5 mg of ramipril as a single dose in order to investigate the pharmacokinetics and excretion pattern of ramipril. All patients had a T-drainage that allowed bile collection. Serum was collected at regular intervals, bile was collected hourly for 6 h followed by a 6- and 12-h fraction, and urine was collected every 2 h for 8 h followed by a 4- and 12-h fraction. The concentrations of ramipril and ramiprilat in serum and ramipril, ramiprilat, ramipril glucuronide, ramiprilat glucuronide, diketopiperazine, and diketopiperazine acid in bile and urine were determined and the amounts excreted in urine and bile over 24 h were calculated. There were great interindividual differences in maximum concentrations as well as in the time to reach maximum concentrations in plasma and bile as well as in the excretion pattern between urine and bile. The highest concentrations in bile were found for diketopiperazine acid (3,080 ng/ml) and ramipril glucuronide (2,414 ng/ml). In general, only minimal amounts of unchanged ramipril (prodrug) were detected in the bile. In the urine, the major metabolites excreted were diketopiperazine acid, ramiprilat, and diketopiperazine in amounts of 537, 188, and 124 micrograms, respectively. In bile, the main substances excreted were diketopiperazine acid and ramiprilat glucuronide, which amounted to 501 and 314 micrograms, respectively. Biliary excretion may be the explanation for the noncomplete urinary recovery of ramipril and its metabolites.
