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Vol. 295, Issue 2, 512-518, November 2000
Rats1
Division of Drug Delivery and Disposition, School of Pharmacy
(H.X., K.C.T., K.L.R.B.) and Curriculum in Toxicology, School of
Medicine (E.S.W., K.L.R.B.), University of North Carolina at Chapel
Hill, Chapel Hill, North Carolina; and Division of Gastroenterology and
Hepatology, University Hospital, Gröningen, The Netherlands
(P.L.M.J.)
Previous studies have demonstrated that phenobarbital treatment impairs
the biliary excretion of acetaminophen glucuronide (AG), although the
transport system(s) responsible for AG excretion into bile has not been
identified. Initial studies in rat canalicular liver plasma
membrane vesicles indicated that AG uptake was stimulated modestly by ATP, but not by membrane potential,
HCO3
, or pH gradients. To examine the role of
the ATP-dependent canalicular transporter multidrug
resistance-associated protein 2 (Mrp2)/canalicular multispecific
organic anion transporter (cMOAT) in the biliary excretion of AG, the
hepatobiliary disposition of acetaminophen, AG, and acetaminophen
sulfate (AS) was examined in isolated perfused livers from control and
TR (Mrp2-deficient) Wistar rats. Mean bile flow in
TR livers was ~0.3 µl/min/g of liver (~4-fold lower
than control). AG biliary excretion was decreased (>300-fold) to
negligible levels in TR rat livers, indicating that AG is
an Mrp2 substrate. Similarly, AS biliary excretion in TR
livers was decreased (~5-fold); however, concentrations were still
measurable, suggesting that multiple mechanisms, including Mrp2-mediated active transport, may be involved in AS biliary excretion. AG and AS perfusate concentrations were significantly higher
in livers from TR compared with control rats.
Pharmacokinetic modeling of the data revealed that the rate constant
for basolateral egress of AG increased significantly from 0.028 to
0.206 min1, consistent with up-regulation of a
basolateral organic anion transporter in Mrp2-deficient rat livers. In
conclusion, these data indicate that AG biliary excretion is mediated
by Mrp2, and clearly demonstrate that substrate disposition may be
influenced by alterations in complementary transport systems in
transport-deficient animals.
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