1. Volume 117, Issue 4, Pages 962-971 (October 1999)
Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats 
Ulrich Bolder, Nhan V. Trang, Lee R. Hagey, Claudio D. Schteingart, Huong–thu Ton–nu, Carolina Cerrè, Ronald P.J. Oude Elferink, Alan F. Hofmann 
Gastroenterology 
Volume 117, Issue 4, Pages (October 1999)
DOI: /S (99)
Copyright © 1999 American Gastroenterological Association Terms and Conditions

2. Fig. 1
Chemical structure of sulindac compared with that of nor-UDCA. Both are weak acids with a pKa of approximately 5. Sulindac has 1 polar group (a methylsulfinyl group), and norursodeoxycholic acid has 2 polar groups (hydroxy groups at C-3 and C-7), in addition to the carboxyl group.
Gastroenterology  , DOI: ( /S (99) )
Copyright © 1999 American Gastroenterological Association Terms and Conditions

3. Fig. 2
(A) Relationship between biliary recovery of sulindac, nor-UDCA, ibuprofen, ketoprofen, norfloxacin, diclofenac, and UDCA (and their corresponding metabolites) (horizontal axis) and bile flow (vertical axis) in anesthetized biliary fistula rats. Only linear regression lines are shown because of overlapping of individual values. The slopes of sulindac and nor-UDCA were significantly higher than the slopes of the other compounds (P < 0.001); these did not differ from each other. Values for the slope (ACA) and the y-intercept are shown in Table 1, which also gives the correlation coefficients of the regression equations. (B) Relationship between biliary recovery of sulindac, nor-UDCA, diclofenac, norfloxacin, ketoprofen, and ibuprofen (and their corresponding metabolites) (horizontal axis) and biliary bicarbonate concentration (vertical axis). A significant increase of bicarbonate concentration was detected for sulindac compared with all other compounds (P < 0.01). The regression equation for sulindac was y = 24.7x (r = 0.86); nor-UDCA, y = 11.7x (r = 0.80); diclofenac, y = 2.5x (r = 0.42); norfloxacin, y = 1.9x (r = 0.81); ketoprofen, y = −0.06x (r = 0.91); and ibuprofen y = −2.3x (r = 0.37).
Gastroenterology  , DOI: ( /S (99) )
Copyright © 1999 American Gastroenterological Association Terms and Conditions

4. Fig. 3
(A) Time course of biliary recovery of a bolus dose (5 μmol/infusion time, < 5 seconds) of sulindac in the isolated rat liver perfused in single-pass mode (○) or recirculating mode (●). (Cholyltaurine was infused continuously at 1 μmol · kg−1 · min−1 to maintain a stable baseline bile flow.) Biliary recovery of sulindac was prolonged, especially in the recirculating mode. (B) Effect of a bolus of sulindac on bile flow in the isolated liver perfused in single-pass mode (○) or recirculating mode (●). Choleresis was vigorous and prolonged, especially in the recirculating mode, consistent with cholehepatic shunting of sulindac. In both studies, a tracer dose of [3H]cholyltaurine (▴) was infused as a bolus (infusion time, < 5 seconds) to define the kinetics of secretion of a molecule using bile acid transporters but not undergoing a cholehepatic circulation.
Gastroenterology  , DOI: ( /S (99) )
Copyright © 1999 American Gastroenterological Association Terms and Conditions

5. Fig. 4
(A) Effect of superimposing an infusion of cholyltaurine (CT) on a continuous infusion of sulindac on sulindac output (●) and bile flow (○) in anesthetized biliary fistula rats (n = 3). Sulindac was infused at a dose of 0.5 μmol · kg−1 · min−1. When steady-state conditions were reached for bile flow and sulindac output, cholyltaurine was given at a dose of 5 μmol · kg−1 · min−1. A significant reduction of sulindac secretion was detected (*P < 0.03), indicating that cholyltaurine inhibited sulindac transport through the hepatocyte. Sulindac output returned to normal after the bile acid infusion was stopped. (B) Effect of superimposing a dose of UDCA (5 μmol · kg−1 · min−1) and taurine (25 μmol · kg−1 · min−1) on a continuous infusion of sulindac (0.5 μmol · kg−1 · min−1) on sulindac output (●) and bile flow (○) in anesthetized biliary fistula rats (n = 3). The unconjugated bile acid infusion caused increased sulindac recovery (*P < 0.05) without hypercholeresis, suggesting that inhibition of sulindac transport by cholyltaurine occurs at the uptake step.
Gastroenterology  , DOI: ( /S (99) )
Copyright © 1999 American Gastroenterological Association Terms and Conditions

6. Fig. 5
(A) Time course of biliary recovery of intravenously administered sulindac (5 μmol · kg−1 · min−1) in Tr− rats (●) (n = 4) and control rats (○). Identical kinetics of excretion indicate that biliary secretion of sulindac does not require the canalicular transporter mrp2 (cMOAT), because this is absent in Tr− rats. (B) Time course of bile flow in Tr− and control rats; no difference was observed.
Gastroenterology  , DOI: ( /S (99) )
Copyright © 1999 American Gastroenterological Association Terms and Conditions

7. Fig. 6
Experiments in the isolated perfused liver (single-pass mode) showing time course of test molecule recovery, bile flow, and biliary bicarbonate output. (A and B) Effect of superimposing a sulindac infusion (5 μmol · kg−1 · min−1) on a continuous infusion of cholyltaurine (1 μmol · kg−1 · min−1). BAR, bile acid recovery. (A) Time course of bicarbonate concentration (▵), bicarbonate output (2), and sulindac recovery (■). Infusions were well tolerated without any signs of toxicity. (B) Time course of bile flow (○) and cholyltaurine recovery (●). At this infusion rate, sulindac induced hypercholeresis; the increases in bicarbonate concentration and output and bile flow were significant (★, P < 0.01). The sulindac infusion had only a minimal influence on cholyltaurine recovery in bile. (C and D) Effect of superimposing a higher dose of sulindac (10 μmol · kg−1 · min−1) on a higher dose of cholyltaurine (10 μmol · kg−1 · min−1) in the isolated perfused rat liver. (Both doses were nontoxic when compounds were infused separately.) (C) Time course of sulindac recovery (■); sulindac recovery was much less than the infused dose. (D) Time course of cholyltaurine recovery (●) and bile flow (○). The coinfusion of sulindac caused cholyltaurine recovery to decrease to nearly zero (†P < 0.001) and bile flow decreased markedly (*P < 0.01), indicating acute cholestasis.
Gastroenterology  , DOI: ( /S (99) )
Copyright © 1999 American Gastroenterological Association Terms and Conditions

8. Fig. 7
(A) bLPMs. Lineweaver–Burk plot showing inhibition of initial sodium-dependent uptake of cholyltaurine by sulindac in bLPMs. Vesicles were incubated for 5 seconds in media with and without sodium ion, as described previously.20 The media also contained cholyltaurine (5, 10, 20, or 30 μmol/L). Sulindac concentration in the media was 0 (○), 200 (♢), and 600 (▵) μmol/L. Sodium-dependent uptake was defined as uptake in the presence of Na+ minus uptake in the absence of Na+. Points are means of triplicate determinations using 3 different vesicle preparations. Sulindac inhibited sodium-dependent cholyltaurine uptake in a competitive manner. The calculated Ki value was 750 μmol/L. (B) cLPMs. Lineweaver–Burk plot depicting inhibition of initial uptake of cholyltaurine by sulindac in cLPMs. Vesicles were incubated for 20 seconds in media prepared with or without ATP (sucrose was substituted for ATP).20 Cholyltaurine was included in concentrations of 5, 10, 20, or 30 μmol/L. Sulindac concentrations were 0 (○) or 600 (♢) μmol/L. Net uptake in cLPMs was calculated as uptake in the presence of ATP minus uptake in its absence. Data points are the means of triplicate determinations using 3 different vesicle preparations. Sulindac inhibited ATP-dependent uptake of cholyltaurine by cLPMs in a competitive manner. The calculated Ki value was 1000 μmol/L.
Gastroenterology  , DOI: ( /S (99) )
Copyright © 1999 American Gastroenterological Association Terms and Conditions