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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
Hepatic disposition of 5 (and
6)-carboxy-2',7'-dichlorofluorescein (CDF) and its diacetate
promoiety (CDFDA) was studied in isolated perfused rat livers. Livers from
Wistar wild-type and multidrug resistance-associated protein (Mrp)2-deficient
(TR–) rats were perfused with CDF in the presence or absence
of probenecid. Probenecid decreased the recovery of CDF in bile 
4-fold in
wild-type livers (65 ± 8% versus 15 ± 2% of dose over 2 h). In
livers from TR– rats, CDF was not excreted into bile and
probenecid decreased perfusate CDF concentrations in a concentration-dependent
manner, in part due to inhibition of Mrp3. Plasma membrane vesicles from rat
Mrp2- or Mrp3-transfected Sf9 cells were used to confirm that CDF is a
substrate for Mrp2 and Mrp3; probenecid inhibited the transport of CDF by Mrp2
and Mrp3 in a concentration-dependent manner. CDF uptake in collagen
sandwich-cultured rat hepatocytes was temperature-dependent and saturable
(Km = 22 ± 10 µM; Vmax = 97
± 9 pmol/min/mg protein). Uptake of CDF in sandwich-cultured rat
hepatocytes was impaired significantly by bromosulfophthalein, a substrate for
organic anion-transporting polypeptides (Oatps), but was not modulated by
specific Oatp2 or organic anion transporter (Oat) substrates. CDFDA uptake was
not saturable, temperature-dependent, or impaired by inhibitors. The
hydrolysis of CDFDA to CDF is mediated by basic pH and esterases in biological
media. CDFDA passively diffuses into hepatocytes where it is hydrolyzed to
CDF. In contrast, CDF appears to be taken up by Oatp-mediated transport into
rat hepatocytes and effluxed via Mrp2 into bile and via Mrp3 into sinusoidal
blood.
Address correspondence to: Dr. Kim L. R. Brouwer, Division of Drug Delivery and Disposition, School of Pharmacy, CB# 7360, Kerr Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. E-mail: kbrouwer{at}unc.edu
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