Method for Determining Identity:H NMR Spectroscopic and HPLC Analysis
TLC Conditions:SiO2; Dichloromethane: Methanol: NH4OH; 5ml: 5ml: 3 drops; Visualized with AMCS; Single spot; Rf=0.50
A metabolite of Perindoprilat, an angiotensin-converting enzyme (ACE) inhibitor
The bindings of perindopril and of its active metabolite perindoprilat to human serum, isolated proteins and to erythrocytes were studied by equilibrium dialysis. Within the therapeutic concentrations range, perindopril was 74% bound to serum involving a non-saturable process, NKa = 2.87. The main binders are serum albumin and alpha 1-acid glycoprotein. The serum binding of perindoprilat involved two successive steps. First, a saturable high-affinity binding (Ka: 2.8 x 10(9) M-1) occurred, involving probably the angiotensin converting enzyme (ACE). The second binding step was non-saturable with a very weak binding capacity, NKa = 0.15, quite superimposable to the HSA bound perindoprilat. Free fatty acids (FFA) did not alter the binding to HSA. The binding of both compounds to erythrocytes was low especially with perindopril, when measured in the presence of plasma. A significant correlation showed that the overall serum binding percentage of both drugs was essentially determined by HSA concentration. Serum binding was decreased in renal failure or cirrhosis, this result was principally linked to the hypoalbuminemia. Interactions with other drugs were limited to the binding of salicylate, tolbutamide and digitoxin to HSA.
1. Perindopril is a prodrug which is hydrolysed in vivo to the active metabolite perindoprilat, an angiotensin-converting enzyme inhibitor. Perindoprilat glucuronide is also found in plasma. 2. The pharmacokinetics of perindopril and its metabolites were studied after administration of a single 4mg dose to hypertensive patients with various degrees of renal failure. 3 The absorption and elimination of perindopril were not influenced by the degree of renal failure. 4 The mean area under the serum concentration-time curve of the active metabolite perindoprilat increased from 93ng ml-1 h in subjects with normal renal function to 1106ng ml-1 in patients with severe renal failure, whereas its half-life varied from 5.0 to 27.4h. 5 In the same subjects, the mean area under the curve of perindoprilat glucuronide increased from 78 to 513ng ml-1 h, while its half-life varied from 1.8 h to 7.7 h. 6 Perindopril, perindoprilat, and perindoprilat glucuronide were dialysable. 7 The extent and duration of serum angiotensin-converting enzyme inhibition was augmented in renal failure. The mean area under the inhibition time curve (extrapolated to infinity) increased from 2490%.h in subjects with normal renal function to 42241 %.h in patients with severe renal impairment. The half-life of inhibition varied from 12.1 h to 100.4 h. This effect of renal failure on the pharmacodynamics of perindoprilat was more pronounced than its influence on perindoprilat kinetics. 8 In view of the important influence of renal impairment on the elimination and action of the active substance perindoprilat, a dosage reduction of perindopril is proposed in in patients with renal failure.
Storage and Stability:May be stored at RT for short-term only. Long-term storage is recommended at -20°C. For maximum recovery of product, centrifuge the original vial prior to removing the cap.
