title: High affinity uptake by isolated rat hepatocytes of a linear pseudo-hexapeptide, ditekiren.
abstract: 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.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6600, USA. richard.kim@mcmail.vanderbilt.edu
authors.forename: R B
authors.initials: RB
authors.lastname: Kim
authors.forename: P R
authors.initials: PR
authors.lastname: Perry
authors.forename: G R
authors.initials: GR
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology; D010634:Phenobarbital / Q000008:administration & dosage; D011480:Protease Inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium
chemical_list: D004151:Dipeptides; D009842:Oligopeptides; D011480:Protease Inhibitors; D011743:Pyrimidines; D014316:Tritium; C070401:EMD 51921; C050898:ditekiren; D010634:Phenobarbital