Chemical formula: C₂₄H₃₄N₂O₅ Molecular mass: 430.537 g/mol PubChem compound: 5484727
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.
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.
Trandolapril is very rapidly absorbed after oral administration. The amount absorbed is equivalent to 40 to 60% of the administered dose and is not affected by food consumption.
The peak plasma concentration of trandolapril is observed 30 minutes after administration. Trandolapril disappears rapidly from the plasma with a half-life of less than one hour.
Trandolapril is hydrolysed to trandolaprilat, a specific ACE inhibitor. The amount of trandolaprilat formed is not modified by food consumption. The median peak plasma concentration values of trandolaprilat are reached after 3 to 8 hours. The absolute bioavailability following trandolapril dose is about 13%.
In the plasma, trandolaprilat is more than 80% protein-bound. It binds saturably, with a high affinity, to ACE. The major proportion of circulating trandolaprilat is also nonsaturably bound to albumin.
After repeated administration of trandolapril in a single daily dose, steady state of trandolaprilat is reached on average in four days, both in healthy volunteers and in young or older hypertensives. The effective half-life of trandolaprilat is between 15 and 23 hours. The terminal half-life of elimination is between 47 hours and 98 hours, depending on dose. This terminal phase probably represents binding/dissociation kinetics of the trandolaprilat/ACE complex.
About 9-14% of an administered trandolapril dose is excreted as trandolaprilat in urine. A negligible amount of trandolapril is excreted unchanged in the urine (<0.5%). After oral administration of the labelled product in man, 33% of the radioactivity is found in the urine and 66% in the faeces.
Trandolapril pharmacokinetics have not been evaluated in patients less than 18 years of age.
Trandolapril pharmacokinetics have been investigated in older people (over 65 years) and in both genders. The plasma concentration of trandolapril is increased in older hypertensive patients, but the plasma concentration of trandolaprilat and inhibition of ACE activity are similar in old and young hypertensive patients.
The pharmacokinetics of trandolapril and trandolaprilat and inhibition of ACE activity are similar in older male and female hypertensive patients.
Compared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately two-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 mL/min and in patients on haemodialysis. Dosage adjustment is recommended in renal impaired patients.
Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, nine-fold and two-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency.
Acute oral toxicity studies of trandolapril and its active metabolite, trandolaprilat, in rats and mice showed both compounds to be non-toxic with respective LD50 values of >4000 mg/kg and >5000 mg/kg.
Repeat dose oral toxicity was evaluated in the rat and dog with studies of up to 18 and 12 months' duration, respectively.
The principal observations in these studies were of anaemia (doses of 20 mg/kg/day and above in the rat 30-day study and 25 mg/kg/day and above in the dog 6-month study), gastric irritation and ulceration (doses of 20 mg/kg/day and above in the rat 30-day study and 125 mg/kg/day in the dog 6-month study) and renal lesions (20 mg/kg/day and above in the rat 30-day study and 10 mg/kg/day in the dog 30-day study). Renal lesions were also seen in the 6-month studies in the rat and dog (from doses of 0.25 and 25 mg/kg/day, respectively); these were reversible on cessation of treatment.
Reproduction toxicity studies showed effects on renal development in offspring with increased incidence of renal pelvic dilation; this was seen at doses of 10 mg/kg/day and above in the rat but these changes did not affect the normal development of the offspring.
Trandolapril was not mutagenic or carcinogenic.
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