Disposition of zofenopril calcium in healthy subjects

Zofenopril calcium (1) is a prodrug that is hydrolyzed in vivo to the active angiotensin-converting enzyme (ACE) inhibitor SQ 26,333 (2). In a two-way crossover study, six healthy male subjects (age range 25–36 years) each received an iv 11.2-mg dose of [¹⁴C]SQ 26,703 (¹⁴C-3; the L-arginine salt of 2) and an oral 10-mg (equimolar) dose of ¹⁴C-1. After the iv dose of ¹⁴C-3, the 0–96-h recovery of radioactivity averaged 76 and 16% of the dose in urine and feces, respectively, indicating substantial biliary secretion. After the oral dose of ¹⁴C-1, excretion of radioactivity averaged 70% (urine) and 26% (feces). Negligible amounts of 1 were present in urine, indicating complete hydrolysis of the orally administered prodrug. The oral absorption of 1 was almost complete and the oral bioavailability of 2 averaged ∽70%. The terminal elimination half-life for 2 after the iv dose averaged 5.5 h. Whole body clearance, renal clearance, nonrenal clearance, and Vd_ss averaged 11.4, 3.1, and 8.3 mL/min/kg and 1.3 L/kg, respectively. These data indicated that 2 is eliminated by the kidney as well as the liver, is extensively metabolized, and is distributed extensively into extravascular sites.