RT Journal Article
SR Electronic
T1 MULTIPLE TRANSPORT SYSTEMS MEDIATE THE HEPATIC UPTAKE AND BILIARY EXCRETION OF THE METABOLICALLY STABLE OPIOID PEPTIDE [<span class="sc">d</span>-PENICILLAMINE<sup>2,5</sup>]ENKEPHALIN
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 287
OP 293
DO 10.1124/dmd.104.001420
VO 33
IS 2
A1 Hoffmaster, Keith A.
A1 Zamek-Gliszczynski, Maciej J.
A1 Pollack, Gary M.
A1 Brouwer, Kim L. R.
YR 2005
UL http://dmd.aspetjournals.org/content/33/2/287.abstract
AB Rapid and extensive biliary excretion of [d-penicillamine2,5]enkephalin (DPDPE) in rats as the unchanged peptide suggests that multiple transport proteins may be involved in the hepatobiliary disposition of this zwitterionic peptide. Although DPDPE is a P-glycoprotein substrate, the role of other transport proteins in the hepatic clearance of DPDPE has not been established. Furthermore, the ability of various experimental approaches to quantitate the contribution of a specific hepatic uptake or excretion process when multiple transport systems are involved has not been addressed. 3H-DPDPE uptake in suspended Wistar rat hepatocytes was primarily (&gt;95%) due to temperature-dependent transport mechanisms; similar results were obtained in suspended hepatocytes from Mrp2-deficient (TR-) rats. Pharmacokinetic modeling revealed that saturable and linear processes were involved in 3H-DPDPE uptake in hepatocytes. The use of transport modulators suggested that hepatic uptake of 3H-DPDPE was mediated by Oatp1a1, Oatp1a4, and likely Oatp1b2. Accumulation of 3H-DPDPE in sandwich-cultured (SC) hepatocytes was rapid; uptake of 3H-DPDPE in SC rat hepatocytes from control and TR- rats was similar. However, the biliary excretion index and biliary clearance decreased by 83 and 85%, respectively, in TR- SC rat hepatocytes, indicating that DPDPE is an Mrp2 substrate. Rate constants for uptake and excretion of 3H-DPDPE in SC rat hepatocytes were determined by pharmacokinetic modeling; data were consistent with basolateral excretion of 3H-DPDPE from the hepatocyte. These results demonstrate the complexities of hepatobiliary disposition when multiple transport mechanisms are involved for a given substrate and emphasize the necessity of multi-experimental approaches for the comprehensive resolution of these processes. The American Society for Pharmacology and Experimental Therapeutics