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Vol. 304, Issue 1, 223-228, January 2003
Division of Clinical Pharmacology, Vanderbilt University School of
Medicine, Nashville, Tennessee (R.G.T., B.F.L., R.B.K.); and Marion
Bessin Liver Research Center, Albert Einstein College of Medicine,
Bronx, New York (A.W.W.)
Rifampin, a member of the rifamycin class of antibiotics, is well known
for its ability to induce drug-metabolizing enzymes and transporters,
through activation of the pregnane X receptor. Available data suggest
rifampin entry into hepatocytes may be transporter-mediated.
Accordingly, it is therefore plausible that modulation of the
achievable intracellular concentration of rifampin by drug uptake
transporters would influence the degree of induction. In this study, we
expressed an array of known hepatic uptake transporters to show the key
hepatic rifampin uptake transporters are liver-specific members of the
organic anion transporting polypeptide family (OATP). Indeed, both
OATP-C and OATP8 seemed capable of mediating rifampin uptake into HeLa
cells. OATP-C, however, seemed to have far greater affinity and
capacity for rifampin transport. In addition, several allelic variants
of OATP-C known to be present among European and African Americans were
found to have markedly decreased rifampin transport activity. In
cell-based, transactivation assays, OATP-C expression was associated
with increased cellular rifampin retention as well as potentiation of
PXR reporter gene activity. This is the first demonstration of an
uptake transporter such as OATP-C, in modulating PXR function, and
sheds important new insight into our understanding of the molecular
determinants of PXR-mediated inductive processes.
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