Sites of First-Pass Bioactivation (Hydrolysis) of Orally Administered Zofenopril Calcium in Dogs

The relative contribution of the gut, liver, and lungs as sites of first-pass bioactivation (hydrolysis) of the orally administered ester prodrug, zofenopril calcium (SQ 26,991), to the active angiotensin converting enzyme (ACE) inhibitor, SQ 26,333, was determined. With a five-way study design, two dogs each received a single 1.6-mg/kg dose of zofenopril as its soluble potassium salt (SQ 26,900)] via the following routes of administration: intraarterial, intravenous, intraportal, and oral. Each dog also received an equimolar oral dose of zofenopril calcium (1.5 mg/kg). Concentrations of zofenopril in plasma were quantitated with a GC/MSD assay. Extraction ratios (E) for zofenopril by the gut, liver, and lungs were calculated based on the ratios of the area under the curve (AUC) values of zofenopril in arterial plasma after administration by the various routes. As individual eliminating organs, the gut and liver each had a high intrinsic capability to hydrolyze zofenopril; E values ranged from 45 to 89%. The lungs were found to have low, but measurable, hydrolytic activity with estimated E values that ranged from 5 to 26%. Overall, about 95% of the orally administered dose of zofenopril calcium was hydrolyzed during the first pass. Because the prodrug is sequentially exposed to the gut, liver, and lungs, the contribution of the gut to the overall first-pass hydrolysis (ca. 87%) was estimated to be significantly greater than that of the liver (<10%) or lungs (<2%). Zofenopril was rapidly eliminated after parenteral administration; mean residence time values were 2 min and the elimination half-life values (intraarterial route only) were 9 min. The total-body clearance (Cl_total) of zofenopril, determined after intraarterial injection, was rapid (ca. 25 ml/min/kg) and was similar to the Cl_total value reported previously for fosinopril sodium, another prodrug ACE inhibitor. Although the E _lungs value was relatively low, the lungs receive 100% of cardiac output and were estimated to contribute significantly to systemic bioactivation of zofenopril. The major sites of systemic bioactivation appear to be the lungs (ca. 44 to 65%) and liver (ca. 31%), whereas the hydrolysis of zofenopril by the blood per se does not apparently contribute to Cl_total.