Abstract

The in vivo fate of U-71038 (Boc-Pro-Phe-N-MeHis-Leu psi [CHOHCH2] Val-Ile-(aminomethyl)pyridine), a potent renin inhibitor, was investigated in rats by single iv administration of tritium-labeled drug at a dose level of 5 mg/kg. The plasma concentrations of drug-related radioactivity diminished very rapidly during the first hour after dosing, with the initial concentrations measured at 2 min falling by more than 95% during the first 30 min. Estimates of the approximate half-life of this earliest phase of the plasma concentration-time curve gave an average value of 4 min. The residual amount of radioactivity after 30 min was cleared from the plasma more slowly, with trace levels still detected 48 hr after dosing. The radioactivity was recovered chiefly (91% of the dose) in feces, indicating biliary clearance as the primary route of elimination from systemic circulation. Urinary recoveries averaged 4% of the dose. Radio-HPLC profiling of plasma, urine, and bile extracts detected only a single radioactive drug-related component in these samples. Preparative HPLC was used to isolate this component from bile; mass spectral comparison to U-71038 confirmed its identity as the unchanged drug. Therefore, U-71038 does not undergo significant systemic metabolism in this species and is eliminated in bile and urine in intact form. Distribution of drug-related radioactivity was very rapid to most of the organs and tissues that were sampled, with the exception of very limited penetration into the central nervous system. Highest tissue levels of tritium were generally found in organs associated with elimination (liver, intestine, kidney) and in thyroid.