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Vol. 27, Issue 6, 637-644, June 1999
Division of Drug Delivery and Disposition, School of Pharmacy,
University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina (X.L., E.L.L., K.L.R.B.); and Division of Bioanalysis and
Drug Metabolism, Glaxo Wellcome, Inc., Research Triangle Park, North
Carolina (J.P.C., K.R.B.)
The relationship between biliary excretion in sandwich-cultured rat
hepatocytes and in vivo in rats was examined. The biliary excretion of seven model substrates in 96-h sandwich-cultured rat
hepatocytes was determined by differential cumulative uptake of
substrate in the monolayers preincubated in standard buffer (intact
bile canaliculi) and Ca2+-free buffer (disrupted bile
canaliculi). Biliary excretion in vivo was quantitated in bile
duct-cannulated rats. The biliary excretion index of model substrates,
equivalent to the percentage of retained substrate in the canalicular
networks, was consistent with the percentage of the dose excreted in
bile from in vivo experiments. The in vitro biliary clearance of
inulin, salicylate, methotrexate,
[D-pen2,5]enkephalin, and taurocholate,
calculated as the ratio of the amount excreted into the bile
canalicular networks and the area under the incubation medium
concentration-time profile (~0, ~0, 4.1 ± 1.0, 12.6 ± 2.2, and 56.2 ± 6.0 ml/min/kg, respectively), correlated with
their intrinsic in vivo biliary clearance (0.04, 0, 17.3, 34.4, and
116.9 ml/min/kg, respectively; r2 = 0.99). The model
compound 264W94 was not excreted in bile either in vivo or in vitro.
The glucuronide conjugate of 2169W94, the O-demethylated metabolite of 264W94, was excreted into bile
in vitro when 2169W94, but not 264W94, was incubated with the
monolayers; 2169W94 glucuronide undergoes extensive biliary
excretion after administration of 264W94 or 2169W94 in vivo.
Biliary excretion in long-term sandwich-cultured rat hepatocytes
correlates with in vivo biliary excretion. The study of biliary
excretion of metabolites in the hepatocyte monolayers requires
consideration of the status of metabolic activities.
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