Chemical formula: C₂₂H₂₃NO₄S₂ Molecular mass: 429.55 g/mol PubChem compound: 92400
The beneficial effects of zofenopril in hypertension and acute myocardial infarction appear to result primarily from the suppression of the plasma renin-angiotensin aldosterone system. Inhibition of ACE (Ki 0.4nM in rabbit lung for arginine salt of zofenoprilat) results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to reduced aldosterone secretion. Although the latter decrease is small, small increases in serum potassium concentrations may occur, along with sodium and fluid loss. The cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity. The plasma ACE activity is suppressed by 53.4% and 74.4% at 24 hours after administration of single oral doses of 30mg and 60mg zofenopril calcium respectively.
Inhibition of ACE results in an increased activity of circulating and local kallikrein-kininsystem, which contributes to peripheral vasodilatation by activating the prostaglandin system. It is possible that this mechanism is involved in the hypotensive effect of zofenopril calcium and is responsible for certain side effects.
In patients with hypertension, administration of zofenopril results in a reduction of supine and standing blood pressure to about the same extent, with no compensatory increase of the heart rate. Mean systemic vascular resistance tends to decline after zofenopril administration.
Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effects are maintained during long term therapy.
Abrupt withdrawal of therapy has not been associated with a rapid increase in blood pressure. Currently there are no data regarding the effects of zofenopril on morbidity and mortality in hypertensive patients.
Although antihypertensive effects have been found in all races studied, black hypertensive patients (usually a low-renin hypertensive population) has a smaller average response to ACE inhibitor monotherapy than non-black patients. This difference disappears when a diuretic is added.
The clinical effect resulting from the early use of zofenopril following myocardial infarction may be linked to many factors such as the reduction in plasma levels of angiotensin II (in this way limiting the process of ventricular remodelling which can negatively influence the quod vitam prognosis of the infarction patient), and the increase in plasma/tissue concentrations of vasodilator substances (prostaglandins-kinin system).
Zofenopril calcium is a prodrug, since the active inhibitor is the free sulfhydryl compound, zofenoprilat, resulting from thio-ester hydrolysis.
Zofenopril calcium is rapidly and completely absorbed by the oral route and undergoes nearly complete conversion to zofenoprilat, which reaches peak blood levels after 1.5h following an oral dose of zofenopril. Single dose kinetics are linear over a dose-range of 10-80mg of zofenopril calcium and no accumulation occurs after the administration of 15-60mg of zofenopril calcium for 3 weeks. The presence of food in the gastrointestinal tract reduces the rate but not the extent of absorption and the AUCs of zofenoprilat are nearly identical in the fasted or fed state.
Approximately 88% of the circulating radioactivity measured ex-vivo following a radiolabelled dose of zofenopril calcium is bound to plasma protein and the steady state volume of distribution is 96 litres.
Eight metabolites, accounting for 76% of the urinary radioactivity, were identified in human urine following a radiolabelled dose of zofenopril calcium. The main metabolite is zofenoprilat (22%), which is then metabolized through several pathways, including glucuronide conjugation (17%), cyclization and glucuronide conjugation (13%), cysteine conjugation (9%) and Smethylation of the thiol group (8%). Half-life of zofenoprilat is 5.5h and its total body clearance is 1300ml/min following oral zofenopril calcium.
Radiolabelled zofenoprilat administered intravenously is eliminated in urine (76%) and faeces (16%) while following an oral dose of radiolabelled zofenopril calcium, 69% and 26% of the radioactivity is recovered in urine and faeces respectively, indicating a dual route of elimination (kidney and liver).
In older people, no dose adjustment is required when the renal function is normal.
Based on comparison of key pharmacokinetic parameters of zofenoprilat measured after oral administration of radiolabelled zofenopril calcium, patients with mild renal impairment (creatinine clearance >45 and <90 ml/min) eliminate zofenopril from the body at the same rate as normal subjects (creatinine clearance >90ml/min). In patients with moderate to severe renal impairment (7-44ml/min), the rate of elimination is reduced to about 50% of normal. This indicates that these patients should be given half the usual starting dose of zofenopril. In patients with end stage renal disease on haemodialysis and peritoneal dialysis, the rate of elimination is reduced to 25% of normal. This indicates that these patients should be given a quarter of the usual starting dose of zofenopril.
In patients with mild to moderate hepatic dysfunction given single doses of radiolabelled zofenopril calcium, the Cmax and Tmax values for zofenoprilat were similar to those in normal subjects. However, AUC values in cirrhotic patients were about twice those obtained for normal subjects, indicating that the initial dose of zofenopril for patients with mild to moderate hepatic dysfunction should be half of that for patients with normal hepatic function. There are no pharmacokinetic data of zofenopril and zofenoprilat in patients with severe hepatic dysfunction, therefore zofenopril is contraindicated in these patients.
In repeat oral dose toxicity studies conducted in three mammalian species most of the treatment related effects where those usually reported for ACE inhibitors. These changes included a decrease in erythrocytic parameters, an increase in serum urea nitrogen, a decrease in heart weight and hyperplasia of the juxta-glomerular cells which occurred at dose levels much higher than the maximum recommended human dose. In a repeat dose oral toxicity study in the dog, species-specific immunologically-mediated blood dyscrasias occurred at high dose levels.
No significant changes in cytochrome P450 enzyme activities have been observed in a 1 year repeated oral toxicity study in the monkey.
In reproductive toxicity studies, zofenopril caused a dose related reduction in growth rate in offspring and also nephrotoxicity and reduced postnatal viability at dose levels of 90 and 270mg/kg in the F1 generation. Treatment with zofenopril during pregnancy caused feetal and developmental toxicity in offspring in the rat and also embryo- and feto-toxicity in the rabbit but only at maternally toxic dose levels.
Genotoxicity studies showed that zofenopril was not mutagenic or clastogenic.
Carcinogenicity studies conducted in mice and rats revealed no evidence of carcinogenicity. An increased incidence of testicular atrophy occurred only in the mouse study, the clinical significance of which is unknown.
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