Trandolapril

Trandolapril is a prodrug, which is rapidly, non-specifically hydrolysed to its potent, long-acting active metabolite, trandolaprilat (other metabolites are inactive) and acts as an orally-active angiotensin converting enzyme inhibitor (ACE inhibitor) without a sulphydryl group. In addition to inhibition of plasma ACE, trandolapril has been experimentally shown to inhibit tissue ACE (particularly vascular, cardial and adrenal). The clinical relevance of tissue ACE inhibition has not been established in humans.

The angiotensin converting enzyme is a peptidyl-dipeptidase, which catalyses the transformation of angiotensin I to the vasoconstrictive angiotensin II and promotes metabolism of bradykinin to inactive fragments.

Small doses of trandolapril induce a potent ACE inhibition, which reduces the angiotensin II production, decreases the aldosterone secretion and increases plasma renin activity by inhibition of the negative feedback regulation.

Trandolapril thus modulates the renin/angiotensin/aldosterone system, which plays a significant role in regulating blood volume and blood pressure.

Inhibition of bradykinin degradation, prostaglandin release and reduced activity in the sympathetic nervous system are other mechanisms of action which may be of importance for ACE inhibitors' vasodilatory activity.

Pharmacodynamic effects

The properties of trandolapril may explain the results obtained in the regression of cardiac hypertrophy with improvement of diastolic function, and improvement of arterial compliance in humans. In addition, a decrease in vascular hypertrophy has been shown in animals.

The drop in peripheral resistance induced by trandolapril is accompanied neither by fluid and salt retention nor by tachycardia.

In hypertensive patients trandolapril reduces the systolic and diastolic blood pressure. Trandolapril has an antihypertensive activity which is independent of the plasma renin level.

In humans the antihypertensive effect of trandolapril is evident about 1 hour after administration, and persists for at least 24 hours, enabling dosage once daily. Trandolapril does not affect the circadian (24-hour) rhythm of the blood pressure.

The antihypertensive effect is maintained during long term treatment without the development of tolerance. There is no rebound effect after discontinuation of treatment. Trandolapril treatment is accompanied by a higher score in evaluating the quality of life.

Combination with a diuretic or a calcium antagonist potentiates the antihypertensive effect of trandolapril.

Absorption

Trandolapril is absorbed rapidly after oral administration. The amount absorbed is equivalent to 40 to 60% of the administered dose and is not affected by food consumption. About 36% of the absorbed amount is converted to trandolaprilat. The bioavailability of trandolaprilat is about 13% following oral administration of trandolapril.

Distribution

Peak plasma concentration for trandolapril is achieved about 30 minutes after administration. Trandolapril disappears rapidly from the plasma with a half-life of less than one hour.

Biotransformation

Trandolapril is hydrolysed to the active metabolite trandolaprilat, a specific ACE (angiotensin converting enzyme) inhibitor. The amount of trandolaprilat formed is not modified by food consumption. Peak plasma concentration for trandolaprilat is reached 3 to 8 hours after administration.

In the plasma, trandolaprilat is more than 80% protein-bound. It binds saturably, with a high affinity, to ACE. Trandolaprilat is also non-saturably bound to albumin.

After repeated administration of single daily doses of trandolaprilat, steady state was reached on average in four days, both in healthy volunteers and in young or older hypertensives as well as patients with cardiac insufficiency. The effective half-life of trandolaprilat accumulation is between 15 and 23 hours.

Elimination

Excretion of non-metabolised trandolaprilat in the urine accounts for 10-15% of the dose administered. After oral administration of the labelled product, 33% of the radioactivity is found in the urine and 66% in the faeces. Renal clearance of trandolaprilat varies from 0.5 to 4 litres per hour, depending on dose.

Renal insufficiency

The renal clearance of trandolaprilat (about 70 ml/min) is proportional to the creatinine clearance. The plasma concentrations of trandolaprilat are significantly higher in patients with a creatinine clearance of ≤30 ml/min and in patients in haemodialysis. A dose adjustment is recommended in these patients.

After repeated dosing in patients with chronic renal failure, steady state is also reached in about four days, whatever the degree of renal failure.

Acute oral toxicity studies of trandolapril and its active metabolite trandolaprilat in rats and mice found both drugs non-toxic with an LD₅₀ values greater than 4,000 mg/kg.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. These include anaemia and gastric irritation and ulceration.

Studies of reproductive toxicity found affected renal development in rat young with increased incidence of renal pelvis dilatation after doses of at least 10 mg/kg/day, but the normal development of the offspring was not affected.

Trandolapril was not mutagenic or carcinogenic.