1 The disposition of two angiotensin converting-enzyme inhibitor drugs was studied in normal volunteers. One drug was enalapril maleate (MK-421), which requires in vivo esterolysis to yield active inhibitor . The other was a lysine analogue of MK-422 (MK-521), which requires no bioactivation. 2 Absorption of enalapril maleate (10 mg, p.o.) was rapid, with peak serum concentrations of enalapril observed 0.5-1.5 h after administration. Based upon urinary recovery of total drug (enalapril plus MK-422), absorption was at least 61%. Bioactivation appeared to be largely post-absorptive. From the ratio of MK-422 to total drug in urine, the minimum extent of bioactivation was estimated at 0.7. 3 A similar dose of MK-521 was absorbed more slowly, reaching peak serum concentrations 6-8 h following drug administration. Minimum absorption, based upon urinary recovery, was 29%. 4 Serum concentration v time profiles for both drugs were polyphasic and exhibited prolonged terminal phases. 5 Recovery in urine and faeces of administered enalapril maleate (intact and as MK-422) was 94%. Recovery of MK-521 was 97%. These results indicate lack of significant metabolism of these agents, apart from the bioactivation of enalapril.

Enalapril, the ethyl ester of a potent angiotensin converting enzyme inhibitor, enalaprilat, was administered to healthy volunteers as a capsule containing 10 mg of the maleate salt, every 24h for eight doses. Serum profiles show little accumulation of enalaprilat following eight daily doses of enalapril maleate. An average effective half-life for accumulation of approximately 11h was calculated from urine data. Comparison of observed 24-h urinary recoveries of enalaprilat to predicted steady-state recovery indicates that an 'average' steady state for enalaprilat is attained by the third or fourth dose of enalapril maleate. Statistical comparison of daily urinary recoveries, as well as Cmin values for enalaprilat, confirm this. Observed fluctuations in serum and urine data during apparent steady state suggest some day-to-day variability in the absorption of enalapril maleate and/or its hydrolysis to enalaprilat. An accumulation ratio of 1.3 for enalaprilat was calculated from the predicted steady-state urinary recovery and observed urinary recovery for dose one.

When three intravenous doses of lisinopril were administered to healthy volunteers, area under the curve (to infinity) vs dose was linear with a positive intercept. Subtracting area under the extrapolated terminal phase of the serum profile from zero to infinity retained the linear relationship, but shifted the regression line to a zero intercept. It is postulated that the terminal phase reflects binding of drug to angiotensin-converting enzyme (ACE). The half-life for the terminal phase (approximately 40 h) was not predictive of steady-state parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half-life for accumulation was 12.6 h. The mean accumulation ratio was 1.38. Steady state was attained after the second daily dose. The observations in these studies with lisinopril are similar to those reported for enalaprilat, the active metabolite of the ACE inhibitor, enalapril maleate.