Pharmacokinetics and pharmacodynamics of zofenopril in healthy volunteers

This study was carried out to investigate the pharmacokinetics of zofenopri l (CAS 81938-43-4) and zofenoprilat, the behaviour of the angiotensin conve rting enzyme (ACE) (pharmacodynamics) following the administration of zofen opril calcium at the single oral dose of 60 mg in eighteen healthy voluntee rs. This open label, one-way study was carried out in a single centre on 18 hea lthy volunteers. The volunteers received an oral single 60 mg dose of zofen opril calcium following an overnight fast. The tablet was swallowed with 25 0 ml of water. Fasting continued for additional 4 h after dosing and no oth er liquid intake was allowed from 1 h before to 7 h after administration. P lasma concentrations of zofenopril and its active metabolite zofenoprilat a s well as serum ACE activity were measured before drug intake (baseline) an d on timed samples over a 36 h period after dosing by LC-MS-MS, a highly se nsitive, validated method for active moiety concentrations. Peak plasma concentration was reached on average at 1.19 h with zofenopril and at 1.36 h with zofenoprilat. Concentrations then decreased reaching val ues under or close to the limit of quantitation (1 ng . ml(-1) for zofenopr il, 2 ng . ml(-1) for zofenoprilat) from 8 to 16 h after dosing. Complete i nhibition of ACE was seen at the first blood sampling time (1 h) and lasted on average up to 9.44 h. ACE activity then slowly reactivated, but enzyme inhibition continued and was estimated to be 74 % and 56 % at 24 and 36 h f ollowing drug administration, respectively. From these data a complete or almost complete enzyme inhibition is expected with zofenopril given in repealed dose regimen.