Hepatic elimination in the rat of ditekiren (U-71038), a renin inhibitor pseudohexapeptide

Oligopeptides developed as potential therapeutic agents are often limited in their duration of action because of rapid disappearance from the bloodstream, even if they are proteolytically stable. In a number of instances, this involves hepatic elimination via biliary excretion of intact peptide. Knowledge of the processes of such hepatic uptake and secretion and their characteristics is limited. Accordingly, the disposition of the Renin Inhibitor ditekiren--a pseudohexapeptide used as a model agent--was investigated in the isolated perfused rat liver preparation. Disappearance of radioactivity from the perfusate after the rapid addition of a radiolabeled tracer dose (0.11 micrograms) of ditekiren was biexponential. The concomitant administration of increasing doses of unlabeled oligopeptide (0.25 to 5 mg) had no effect on the perfusate's pharmacokinetic parameters, including clearance, 6.82 +/- 0.88 ml/min (mean +/- SD) at a perfusate flow rate of 10 ml/min. However, at the 10 mg dosage level, the concentration-time profile became monoexponential with a half-life of 1.24 +/- 0.48 hr--a value similar to the terminal rate of elimination at lower dosages--and perfusate clearance was reduced by 82%. By contrast, marked dose-dependent changes in the biliary excretion of intact ditekiren were observed when unlabeled doses from 0.25 to 10 mg were administered: the 0 to 2 hr biliary recovery decreasing from 61.7 +/- 8.9 to 4.3 +/- 1.8%. These findings demonstrate that both the initial uptake into hepatocytes and the subsequent biliary excretion of a linear oligopeptide, such as ditekiren, are nonlinear. This suggests that translocation across the basolateral (sinusoidal) and canalicular membranes involves carrier-mediated processes.(ABSTRACT TRUNCATED AT 250 WORDS)