Hepatobiliary elimination of certain peptide-mimicking drugs: linear hydrophobic and hydrophilic renin-inhibitors and hydrophobic cyclopeptides.
Kinetic investigations on the hepatocellular uptake of certain peptide-mimicking drugs revealed that in most cases carrier-mediated mechanisms are responsible for their rapid extraction from portal blood. The driving forces for uptake, however, are unknown. Uptake is not dependent on the presence of sodium ions. The membrane potential or other energy sources may drive their uphill transport. Efforts to isolate the transport proteins involved in hepatocellular uptake using the Xenopus laevis oocyte system failed due to high unspecific binding of the peptides. Intracellular cytosolic and membrane-associated binding proteins, however, were isolated and sequenced. Uptake of certain of the drugs investigated is related to the uptake of bile acids. The recently cloned bile acid transporters ntcp and oatp are not the related transport systems. The carrier protein for these peptide-mimicking drugs has yet to be cloned. At the canalicular pole of the cell, excretion of two linear renin-inhibitors EMD 51,921 and CGP 38,560 is due to ATP-dependent transport mechanisms. MDR gene products seem to be involved in the elimination of the renin-inhibitor CGP 38,560, whereas the endogenous ATP-dependent transport system for the renin-inhibitor EMD 51,921 has not been identified.
Ziegler
K
K
Institut für Pharmakologie und Toxikologie, Justus-Liebig Universität Giessen, FRG.
Kolac
C
C
Schulze
S
S
Wenzel
U
U
Kemmer
H
H
D000818:Animals; D001659:Biliary Tract / Q000166:cytology / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics*; D000092502:Renin Inhibitors
D002352:Carrier Proteins; D010455:Peptides; D000092502:Renin Inhibitors