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Vol. 29, Issue 10, 1277-1283, October 2001
Division of Drug Delivery and Disposition, School of Pharmacy,
University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina
Recently, sandwich-cultured (SC) rat hepatocytes have been used as
an in vitro model to assess biliary excretion of drugs and
xenobiotics. The purpose of the present study was to validate the use of SC rat hepatocytes for the in vitro assessment of
P-glycoprotein (P-gp)-mediated biliary drug excretion. The specific and
fluorescent P-gp substrate rhodamine 123 (Rh123) and the P-gp substrate
digoxin were selected as model compounds. Rh123 and digoxin
accumulation and Rh123 efflux under standard and Ca2+-free
conditions were quantified in SC rat hepatocytes to determine substrate
secretion into canalicular networks in vitro. The major role of P-gp in
the biliary excretion of these compounds was confirmed by inhibition
experiments with the potent P-gp inhibitor GF120918. Hepatocyte culture
conditions, including media type and time in culture, significantly
affected Rh123 biliary excretion. P-gp expression, as assessed by
Western blot, was increased with culture time. Dexamethasone (an in
vivo inducer of P-gp) concentrations ranging from 0.01 to 1 µM in the
cell culture medium did not influence P-gp expression or Rh123 biliary
excretion. Rh123 and digoxin biliary clearance values, predicted from
SC rat hepatocyte data, were consistent with values reported in vivo
and in isolated perfused rat liver studies. In conclusion, the results
of this study demonstrate the utility of SC rat hepatocytes as an in
vitro model to study and predict the biliary excretion of P-gp substrates.
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