High affinity uptake by isolated rat hepatocytes of a linear pseudo-hexapeptide, ditekiren

The hepatic elimination of many oligopeptides is both rapid and extensive, and often limits their potential as therapeutic agents. The linear, hydrophobic pseudo-hexapeptide ditekiren, a renin inhibitor, is one such example. The mechanism(s) involved in its hepatic clearance are largely unknown; accordingly, the characteristics of ditekiren's transport into isolated rat hepatocytes was investigated. In addition to a concentration-independent, linear process, uptake also involved a carrier-mediated component (Km = 0.2 +/- 0.05 microM; Vmax = 11.6 +/- 0.6 pmol (mg protein)[-1] min[-1]). Phenobarbital pretreatment in vivo resulted in marked induction of such transport. Negative results from cis-inhibition studies with substrates and/or inhibitors of well-established hepatic transport systems, e.g., sodium-dependent bile acid, sodium-independent multispecific bile acid and cation carriers, ruled out their involvement in ditekiren's uptake. By contrast, a number of cyclic and linear oligopeptides inhibited the uptake process to varying extents and in the case of EMD-59121, the most inhibitory compound, the interaction was competitive in nature. Collectively, these data suggest the presence of a novel high affinity, low capacity transporter in rat hepatocytes with specific affinity for ditekiren and possibly other oligopeptides.