PHARMACOKINETICS, METABOLISM AND BILIARY AND URINARY-EXCRETION OF ORAL RAMIPRIL IN MAN

In order to evaluate the pharmacokinetics and excretion of ramipril in man, 8 cholecystectomy patients aged between 53 and 68 years received 5 mg ramipril orally as a single dose. All patients had a T-drain ins erted to permit bile collection; all gave their informed consent to pa rticipate in the trial. Serum samples were collected half-hourly until 2 hours, then hourly until 6 hours, then at 8, 10, 24 and 25 hours af ter intake. Urine was collected in 2-hour fractions until 8 hours, fol lowed by a 4- and a 12-hour fraction. Bile was collected hourly until 6 hours, followed by a 6- and a 12-hour collecting fraction. Concentra tions of ramipril and ramiprilat in serum, and determinations in urine and bile of ramipril, ramiprilat, ramipril glucuronide, ramiprilat gl ucuronide, diketopiperazine and diketopiperazine acid were made; total amounts excreted were calculated. Peak concentrations of ramiprilat i n plasma (8.7+/-1.6 ng/ml) were reached after about 8 hours. AUC(0-8) and AUC(0-24)-values were 36.5 and 111.9 ng.h/ml, respectively. Ramipr ilat C-max-concentrations were about 300-fold higher in bile than in p lasma, the corresponding difference for ramipril between bile and plas ma was about 4-fold. The main fractions excreted in the urine were dik etopiperazine acid and ramiprilat amounting to 13.2+/-5.6 and 4.4+/-2. 4%, respectively, of the dose administered. Only a very small fraction of the dose was excreted with urine as unchanged ramipril, on average 0.9+/-1.0%. The main fractions excreted in the bile were diketopipera zine acid, ramiprilat glucuronide and diketopiperazine, 9.0+/-5.3, 3.4 +/-4.2 and 2.0+/-1.2% in 24 hours, respectively, of the dose administe red. Only a negligible fraction of the dose (average 0.1+/-0.1%) was e xcreted with bile as unchanged ramipril. In conclusion, there is stron g evidence that circulating ramipril and ramiprilat are eliminated by both the liver and the kidneys. For the patients studied it can be est imated from late collection periods that some 2/3 of circulating ramip ril and ramiprilat are eliminated by the kidneys and 1/3 eliminated by the liver.