Single dose pharmacokinetics of perindopril and its metabolites in hypertensive patients with various degrees of renal insufficiency.
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 4 mg 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 93 ng ml-1 h in subjects with normal renal function to 1106 ng ml-1 in patients with severe renal failure, whereas its half-life varied from 5.0 to 27.4 h. 5 In the same subjects, the mean area under the curve of perindoprilat glucuronide increased from 78 to 513 ng 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Verpooten
G A
GA
Department of Nephrology-Hypertension, University of Antwerp, Edegem, Belgium.
Genissel
P M
PM
Thomas
J R
JR
De Broe
M E
ME
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006977:Hypertension, Renal / Q000378:metabolism*; D007211:Indoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D020913:Perindopril; D006435:Renal Dialysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D005965:Glucuronates; D007211:Indoles; C053500:perindoprilat; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril