Pharmacokinetics, metabolism and biliary and urinary excretion of oral ramipril in man

Abstract

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 inserted to permit bile collection; all gave their informed consent to participate 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 after intake. Urine was collected in 2-hour fractions until 8 hours, followed 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. Concentrations of ramipril and ramiprilat in serum, and determinations in urine and bile of ramipril, ramiprilat, ramipril glucuronide, ramiprilat glucuronide, diketopiperazine and diketopiperazine acid were made; total amounts excreted were calculated. Peak concentrations of ramiprilat in plasma (8.7 +/- 1.6 ng/ml) were reached after about 8 hours. AUC0-8 and AUC0-24-values were 36.5 and 111.9 ng.h/ml, respectively. Ramiprilat Cmax-concentrations were about 300-fold higher in bile than in plasma, the corresponding difference for ramipril between bile and plasma was about 4-fold. The main fractions excreted in the urine were diketopiperazine 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 diketopiperazine 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 administered. Only a negligible fraction of the dose (average 0.1 +/- 0.1%) was excreted with bile as unchanged ramipril. In conclusion, there is strong evidence that circulating ramipril and ramiprilat are eliminated by both the liver and the kidneys. For the patients studied it can be estimated from late collection periods that some 2/3 of circulating ramipril and ramiprilat are eliminated by the kidneys and 1/3 eliminated by the liver.

The Evaluation of Angiotensin-Converting Enzyme Inhibitors in Renal Elimination with Selected Molecular Descriptors

“…Various authors have also suggested several assays that could be employed in investigations of different drug eliminations (30)(31)(32). Most of these methods still have certain limitations, and a new approach for fast, reliable and cost-effective evaluation of the route of elimination of ACE inhibitors should be developed.…”

Human Health Relevance of Pharmaceutically Active Compounds in Drinking Water

“…Approximately 9% of an administered dose of ramipril is eliminated via urine and bile as ramiprilat and its glucuronide conjugate (102). Much like ramipril, ramiprilat has not been monitored to date in Canadian environmental matrices.…”

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

“…It is a monoester carboxylic prodrug with a bioavailability of 50% to 60% extensively and rapidly metabolized to its active diacid derivative, ramiprilat, mainly in the liver. 29 The mechanism by which ramipril and other angiotensin-converting enzyme inhibitors are transported through the gastrointestinal tract remains a matter of debate. 30,31 Whatever the mechanism, the final conversion of ramipril into its active metabolite is not influenced by dietary salt intake.…”