Pharmacokinetics of ITF 296 (Sinitrodil) a novel organic nitrate, in healthy volunteers

ITF 296 is a new orally active nitrate acting selectively on large arterial vessels over a wide range of doses. In healthy volunteers it causes less reduction in vascular resistance and less venodilatation than classic nitrates. Its pharmacokinetic profile was evaluated after intravenous infusion and oral (solution and immediate-release tablet) administration in a randomised cross-over design on 11 healthy volunteers. The plasma levels of ITF 296 and its metabolite ITF 1124 were determined by a HPLC method. The drug is rapidly distributed (mean steady-state distribution volume 53+/-17 liters) and eliminated (half-life of about 25 minutes) both after intravenous and oral administration. The total clearance is 2. 31+/-0.46 l/min. The oral solution of ITF 296 is well absorbed (Cmax=0.057 microg/ml, tmax=30 min) but it undergoes a first-pass effect (F=25%). The tablet, developed only for Phase 1 clinical studies, is characterised by an immediate release (Cmax=0.057 microg/ml, tmax=30 min). The extent of its absolute and relative bioavailability is about 14% and 53% respectively.