THE PHARMACOKINETICS AND PHARMACODYNAMICS OF FOSINOPRIL IN HEMODIALYSIS-PATIENTS

The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibi tor), were investigated in six haemodialysis patients. Intravenous C-1 4-fosinoprilat (7.5 mg), oral C-14-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomiz ed study. Mean maximum concentration (C(max)), clearance (CL), volume of distribution at steady-state (V(ss)), mean residence time (MRT(iv)) , and t1/2 values after IV administration of C-14-fosinoprilat were 2, 042 mug . ml-1, 11.3 ml . min-1, 11.0 l, 16.3 h and 28.3 h, respective ly. Following oral administration of C-14-fosinopril, mean C(max), tim e to maximum plasma concentration (t(max))), and fosinoprilat bioavail ability values were 197 ng . ml-1, 5.2 h and 29.2 %. Para-hydroxy fosi noprilat and fosinoprilat glucuronide comprised approximately 15 % and 2 % of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5 % of the administered dose. The maximu m effect (E(max)) model was fitted to the percentage inhibition of ser um ACE activity vs. fosinoprilat concentration data in three patients. E(max) ranged from 95.3 to 102.5 %, and IC50 (the fosinoprilat concen tration required to produce 50 % of E(max)) ranged from 2.6 to 4.2 ng . ml-1. Pharmacokinetic variables of the patients were similar to thos e in patients with moderate to severe renal dysfunction. Dosage modifi cations or supplemental dosing following dialysis are unnecessary.