Mechanism of Action: ACEONÒ (perindopril erbumine) Tablets is a pro-drug for perindoprilat, which inhibits ACE in human subjects and animals. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium.

ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of ACEONÒ Tablets remains to be elucidated.

While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblacks, a finding consistent with previous experience of other ACE inhibitors.

After administration of perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the maximal inhibition of 80 to 90% attained by 8 mg persisting for 10 to 12 hours. Twenty-four hour ACE inhibition is about 60% after these doses. The degree of ACE inhibition achieved by a given dose appears to diminish over time (the ID₅₀ increases). The pressor response to an angiotensin I infusion is reduced by perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hours after a 12 mg dose.

Pharmacokinetics: Oral administration of ACEONÒ (perindopril erbumine) Tablets results in its rapid absorption with peak plasma concentrations occurring at approximately 1 hour. The absolute oral bioavailability of perindopril is about 75%. Following absorption, approximately 30 to 50% of systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3 to 7 hours after perindopril administration. The presence of food in the gastrointestinal tract does not affect the rate or extent of absorption of perindopril but reduces bioavailability of perindoprilat by about 35%. (See PRECAUTIONS: Food Interaction.)

With 4, 8 and 16 mg doses of ACEONÒ Tablets, Cmax and AUC of perindopril and perindoprilat increase in a linear and dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.

Perindopril exhibits multiexponential pharmacokinetics following oral administration. The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1.0 hours. At very low plasma concentrations of perindopril (<3 ng/mL), there is a prolonged terminal elimination half-life, similar to that seen with other ACE inhibitors, that results from slow dissociation of perindopril from plasma/tissue ACE binding sites. Perindopril does not accumulate with a once-a-day multiple dosing regimen. Mean total body clearance of perindopril is 219 to 362 mL/min and its mean renal clearance is 23.3 to 28.6 mL/min.

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