Moexipril

Moexipril hydrochloride is a prodrug for moexiprilat, which inhibits ACE in humans and animals. The mechanism through which moexiprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator. Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II. Inhibition of ACE results in decreased angiotensin II formation, leading to decreased vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The latter results in diuresis and natriuresis and a small increase in serum potassium concentration (mean increases of about 0.25 mEq/L were seen when moexipril was used alone).

Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood pressure even in apparent low-renin hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of moexipril is considerably smaller in black patients, a predominantly low-renin population, than in non-black hypertensive patients.

Moexipril’s antihypertensive activity is almost entirely due to its deesterified metabolite, moexiprilat. Bioavailability of oral moexipril is about 13% compared to intravenous (I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly affected by food, which reduces the peak plasma level (C_max) and AUC (see Absorption). Moexipril should therefore be taken in a fasting state. The time of peak plasma concentration (T_max) of moexiprilat is about 1 ^1/2 hours and elimination half-life (t_1/2) is estimated at 2 to 9 hours in various studies, the variability reflecting a complex elimination pattern that is not simply exponential. Like all ACE inhibitors, moexiprilat has a prolonged terminal elimination phase, presumably reflecting slow release of drug bound to the ACE. Accumulation of moexiprilat with repeated dosing is minimal, about 30%, compatible with a functional elimination t_1/2 of about 12 hours. Over the dose range of 7.5 to 30 mg, pharmacokinetics are approximately dose proportional.

Absorption

Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about 13%. Bioavailability varies with formulation and food intake which reduces C_max and AUC by about 70% and 40% respectively after the ingestion of a low-fat breakfast or by 80% and 50% respectively after the ingestion of a high-fat breakfast.

Distribution

The clearance (CL) for moexipril is 441 mL/min and for moexiprilat 232 mL/min with a t_½ of 1.3 and 9.8 hours, respectively. Moexiprilat is about 50% protein bound. The volume of distribution of moexiprilat is about 183 liters.

Metabolism and Excretion

Moexipril is relatively rapidly converted to its active metabolite moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t _½ is over one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to diketopiperazine derivatives and unidentified metabolites. After I.V. administration of moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as moexiprilat. After oral administration, only about 7% of the dose appears in urine as moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of the dose is recovered in feces as moexiprilat and 1% as moexipril.

Special Populations

Decreased Renal Function

The effective elimination t_½ and AUC of both moexipril and moexiprilat are increased with decreasing renal function. There is insufficient information available to characterize this relationship fully, but at creatinine clearances in the range of 10 to 40 mL/min, the t_½ of moexiprilat is increased by a factor of 3 to 4.

Decreased Hepatic Function

In patients with mild to moderate cirrhosis given single 15 mg doses of moexipril, the C_max of moexipril was increased by about 50% and the AUC increased by about 120%, while the C_max for moexiprilat was decreased by about 50% and the AUC increased by almost 300%.

Elderly Patients

In elderly male subjects (65 to 80 years old) with clinically normal renal and hepatic function, the AUC and C_max of moexiprilat is about 30% greater than those of younger subjects (19 to 42 years old).

Pharmacokinetic Interactions With Other Drugs

No clinically important pharmacokinetic interactions occurred when moexipril hydrochloride was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine.