Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril

Abstract

The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15%, by ramiprilat plasma AUC, 44%. Ramiprilat formation from intravenous ramipril was 53% and from oral ramipril 28%. Urinary recovery of oral ramipril was 23%, i.v. ramipril 49%, and i.v. ramiprilat 68% of the given dose. Maximum ACE inhibition was highest (100%) after i.v. ramiprilat; it was 99% after i.v. ramipril and 84% following oral ramipril. ACE inhibition over 24 h was highest after i.v. ramipril, 2% less with i.v. ramiprilat and 34% less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44-66%.

Bioanalytical method development and validation using incurred samples—Simultaneous quantitation of ramipril and ramiprilat in human EDTA plasma by LC–MS/MS

“…However, even with this improved condition, it would be extremely difficult to prevent the back-conversion from occuring completely considering the fragile nature of ramipril acyl glucuronide and its relatively high concentration in incurred samples (estimated as high as 60 ng/mL for a single dosage of 10 mg and 8 ng/mL for a single dose of 1.25 mg based on internal data and the reference [3]). In other words, it is unlikely that the amount of ramipril generated by the back-conversion of 60 ng/mL of ramipril Table 4 Validated stabilities of ramipril and ramiprilat using pooled incurred samples.…”

“…1 for chemical structures). The metabolism also yields ramipril and ramiprilat diketopiperazine and various glucuronide metabolites [3][4]. Some of these metabolites, such as acyl and N-glucuronides, are especially labile and are subject to potential back-conversions during sample collection, storage and/or extraction, and after sample processing as well when they are co-extracted.…”

The presence of the top prescribed pharmaceuticals in treated sewage effluents and receiving waters in Southwest Nova Scotia, Canada

“…Both ramipril and quetiapine are heavily metabolized within the body. Ramipril itself is inactive and only 2 % of ramipril is excreted unchanged from the body, although 68 % of an intravenously administered dose is excreted as ramiprilat, the active metabolite (Griensven et al 1995). The Dartmouth STP effluent also showed a high COD (208 mg/L) and low DO (1.41 mg/L).…”

Interference from a glucuronide metabolite in the determination of ramipril and ramiprilat in human plasma and urine by gas chromatography–mass spectrometry

“…Such conjugates had not been found in animal plasma or urine [18] and were not anticipated in human plasma at this stage. Glucuronide conjugates were later identified in human urine [19,20]. One difference between the two methods was that the method giving lower results for ramipril included a washing step after alkylation prior to acylation, the other one did not.…”