Skip to main content
SpringerLink
Log in

Enterohepatic Circulation

Physiological, Pharmacokinetic and Clinical Implications

Clinical Pharmacokinetics volume 41, pages 751–790 (2002)Cite this article

Abstract

Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation. Cycling is often associated with multiple peaks and a longer apparent half-life in a plasma concentration-time profile. Factors affecting biliary excretion include drug characteristics (chemical structure, polarity and molecular size), transport across sinusoidal plasma membrane and canniculae membranes, biotransformation and possible reabsorption from intrahepatic bile ductules. Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria. Bioavailability is also affected by the extent of intestinal absorption, gut-wall P-glycoprotein efflux and gut-wall metabolism.

Recently, there has been a considerable increase in our understanding of the role of transporters, of gene expression of intestinal and hepatic enzymes, and of hepatic zonation. Drugs, disease and genetics may result in induced or inhibited activity of transporters and metabolising enzymes. Reduced expression of one transporter, for example hepatic canalicular multidrug resistance-associated protein (MRP) 2, is often associated with enhanced expression of others, for example the usually quiescent basolateral efflux MRP3, to limit hepatic toxicity. In addition, physiologically relevant pharmacokinetic models, which describe enterohepatic recirculation in terms of its determinants (such as sporadic gall bladder emptying), have been developed.

In general, enterohepatic recirculation may prolong the pharmacological effect of certain drugs and drug metabolites. Of particular importance is the potential amplifying effect of enterohepatic variability in defining differences in the bioavailability, apparent volume of distribution and clearance of a given compound. Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Table I
Table II
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

References

  1. Hofmann AF. The enterohepatic circulation of bile acids in man. Adv Intern Med 1976; 21: 501–34

    PubMed  CAS  Google Scholar 

  2. Plaa GL. Toxic responses of the liver. In: Amdur MO, Doull J, Klaassen CD, editors. Casarett and Doull’s toxicology. New York: Pergamon Press, 1991

    Google Scholar 

  3. Mehendale HM. Hepatotoxicity. In: Haley TJ, Berndt WO, editors. Handbook of toxicology. Washington, DC: Hemisphere, 1987

    Google Scholar 

  4. Laurent A. Analysis in the rat of 4-hydroxynonenal metabolites excreted in bile: evidence of enterohepatic circulation of these byproducts of lipid peroxidation. Chem Res Toxicol 1999; 12: 887–94

    Article  PubMed  CAS  Google Scholar 

  5. Jonsson A, Rydberg T, Sternber G, et al. Pharmacokinetics of glibenclamide and its metabolites in diabetic patients with impaired renal function. Eur J Clin Pharmacol 1998; 53(6): 429–35

    Article  PubMed  CAS  Google Scholar 

  6. Hellstern A, Hildebrand M, Humpel M, et al. Minimal biliary excretion and enterohepatic recirculation of lormetazepam in man as investigated by a new nasobiliary drainage technique. Int J Clin Pharmacol Ther Toxicol 1990; 28(6): 256–61

    PubMed  CAS  Google Scholar 

  7. Melnik G, Schwesinger WH, Teng R, et al. Hepatobiliary elimination of trovafloxacin and metabolites following single oral doses in healthy volunteers. Eur J Clin Microbiol Infect Dis 1998; 17(6): 424–6

    PubMed  CAS  Google Scholar 

  8. Lenzen R, Bahr A, Eichstadt H, et al. In liver transplantation, T tube bile represents total bile flow: physiological and scintigraphic studies on biliary secretion of organic anions. Liver Transpl Surg 1999; 5(1): 8–15

    Article  PubMed  CAS  Google Scholar 

  9. Erlinger S. Review article: new insights into the mechanisms of hepatic transport and bile secretion. J Gastroenterol Hepatol 1996; 11: 575–9

    Article  PubMed  CAS  Google Scholar 

  10. Klaassen CD, Watkins III JB. Mechanisms of bile formation, hepatic uptake, and biliary excretion. Pharmacol Rev 1984; 36: 1–67

    PubMed  CAS  Google Scholar 

  11. Erlinger S. Bile flow. In: Arias IM, Boyer JL, Fausto N, et al., editors. Liver biology and pathobiology. New York: Raven Press, 1994: 769–86

    Google Scholar 

  12. Roberts S, Ludwig J, Larusso N. The pathobiology of biliary epithelia. Gastroenterology 1997; 112: 269–79

    Article  PubMed  CAS  Google Scholar 

  13. Alpini G, Phillips JO, LaRusso NF. The biology of biliary epithelia. In: Arias IM, Boyer JL, Fausto N, et al., editors. Liver biology and pathobiology. New York: Raven Press, 1994: 623–53

    Google Scholar 

  14. Seifter S, Englard S. Energy metabolism. In: Arias IM, Boyer JL, Fausto N, et al., editors. Liver biology and pathobiology. New York: Raven Press, 1994: 323–64

    Google Scholar 

  15. Schaffner F, Popper H. Electron microscopic studies of normal and proliferated bile ductules. Am J Pathol 1961; 38: 393–410

    PubMed  CAS  Google Scholar 

  16. Steiner J, Carruthers J, Kalifat S. The ductular cell reaction of rat liver in extrahepatic cholestasis: I. Proliferated biliary epithelial cells. Exp Mol Pathol 1962; 1: 162–85

    Article  PubMed  CAS  Google Scholar 

  17. Meier PJ. Structural and functional polarity of canalicular and basolateral plasma membrane vesicles isolated in high yield from rat liver. J Cell Biol 1984; 98: 991–1000

    Article  PubMed  CAS  Google Scholar 

  18. Gumbiner B. Structure, biochemistry and assembly of epithelial tight junctions. Am J Physiol 1987; 253: 749–58

    Google Scholar 

  19. Coleman R. Biochemistry of bile secretion. Biochem J 1987; 244: 249–61

    PubMed  CAS  Google Scholar 

  20. Phillips MJ, Poucell S, Oda M. Biology of disease: mechanisms of cholestasis. Lab Invest 1986; 54: 593–608

    PubMed  CAS  Google Scholar 

  21. Phillips M. Intrahepatic cholestasis as a canalicular motility disorder: evidence using cytochalasin. Lab Invest 1983; 48: 205–11

    PubMed  CAS  Google Scholar 

  22. Thompson R, Jansen P. Genetic defects in hepatocanalicular transport. Semin Liver Dis 2000; 20(3): 365–72

    Article  PubMed  CAS  Google Scholar 

  23. Masyuk A. Perfused rat intrahepatic bile ducts secrete and absorb water, solute, and ions. Gastroenterology 2000; 119(6): 1672–80

    Article  PubMed  CAS  Google Scholar 

  24. Marinelli R, Larusso N. Solute and water transport pathways in cholangiocytes. Semin Liver Dis 1996; 16(2): 221–9

    Article  PubMed  CAS  Google Scholar 

  25. Dumont M, Uchman S, Erlinger S. Hypercholeresis induced by ursodeoxycholic acid and 7-ketolithocholic acid in the rat: possible role of bicarbonate transport. Gastroenterology 1980; 79: 82–9

    PubMed  CAS  Google Scholar 

  26. Kitani K, Kanai S. Effect of ursodeoxycholate on the bile flow in the rat. Life Sci 1982; 31: 1973–85

    Article  PubMed  CAS  Google Scholar 

  27. Kanai S, Kitani K, Sato Y. Bile secretory characteristics of beta-muricholate and its taurine conjugate are similar to those of ursodeoxycholate in the rat. Life Sci 1991; 48: 949–57

    Article  PubMed  CAS  Google Scholar 

  28. Sjoqvist F. Fundamentals of clinical pharmacology. In: Speight T, Holford N, editors. Avery’s drug treatment. Auckland: ADIS Press, 1997: 1–73

    Google Scholar 

  29. Doherty M, Pang K. First-pass effect: significance of the intestine for absorption and metabolism. Drug Chem Toxicol 1997; 20(4): 329–44

    Article  PubMed  CAS  Google Scholar 

  30. Yang CY, Dantzig AH, Pidgeon C. Intestinal peptide transport systems and oral drug availability. Pharm Res 1999; 16(9): 1331–43

    Article  PubMed  CAS  Google Scholar 

  31. Florence A, Attwood D. Physicochemical principles of pharmacy. 2nd ed. Wallington: Macmillan Press, 1988

    Google Scholar 

  32. Charman WN. Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci 1997; 86(3): 269–82

    Article  PubMed  CAS  Google Scholar 

  33. Wu C. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporin. Clin Pharmacol Ther 1995; 58: 492–7

    Article  PubMed  CAS  Google Scholar 

  34. Ilett K, Tee LB, Reeves PT, et al. Metabolism of drugs and other xenobiotics in the gut lumen and wall. Pharmacol Ther 1990; 46: 67–93

    Article  PubMed  CAS  Google Scholar 

  35. Hall SD. Molecular and physical mechanisms of first-pass extraction. Drug Metab Dispos 1999; 27(2): 161–6

    PubMed  CAS  Google Scholar 

  36. Roberts M, Rowland M. Hepatic elimination: dispersion model. J Pharm Sci 1985; 74: 585–7

    Article  PubMed  CAS  Google Scholar 

  37. Roberts MS, Anissimov YG, Weiss M. Commentary: using the convection-dispersion model and transit time density functions in the analysis of organ distribution kinetics. J Pharm Sci 2000; 89(12): 1579–86

    Article  PubMed  CAS  Google Scholar 

  38. Iwatsubo T. Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol Ther 1997; 73(2): 147–71

    Article  PubMed  CAS  Google Scholar 

  39. Izumi T. Pharmacokinetics of troglitazone, an antidiabetic agent: prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data. J Pharmacol Exp Ther 1997; 280(3): 1392–400

    PubMed  CAS  Google Scholar 

  40. Ueda K. Enantioselective local disposition of semotiadil (R-enantiomer) and levosemotiadil (S-enantiomer) in perfused rat liver. Drug Metab Dispos 1997; 25(3): 281–6

    PubMed  CAS  Google Scholar 

  41. Kamisako T. Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance. J Gastroenterol 2000; 35(9): 659–64

    Article  PubMed  CAS  Google Scholar 

  42. Kouzuki H, Suzuki H, Sugiyama Y. Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm Res 2000; 17(4): 432–8

    Article  PubMed  CAS  Google Scholar 

  43. Suzuki H, Sugiyama Y. Transport of drugs across the hepatic sinusoidal membrane: sinusoidal drug influx and efflux in the liver. Semin Liver Dis 2000; 20(3): 251–63

    Article  PubMed  CAS  Google Scholar 

  44. Proost J, Roggeveld J, Wierda JM, et al. Relationship between chemical structure and physicochemical properties of series of bulky organic cations and their hepatic uptake and biliary excretion rates. J Pharmacol Exp Ther 1997; 282(2): 715–26

    PubMed  CAS  Google Scholar 

  45. Weisiger R, Fitz J, Scharschmidt B. Hepatic oleate uptake: electrochemical driving forces in the intact rat liver. J Clin Invest 1989; 83: 411–20

    Article  PubMed  CAS  Google Scholar 

  46. Fitz J, Bass N, Weisiger R. Hepatic transport of a fluorescent stearate derivative: electrochemical driving forces in intact rat liver. Am J Physiol 1991; 261: 83–91

    Google Scholar 

  47. Weinman S, Graf J, Boyer J. Voltage-driven, taurocholate-dependent secretion in isolated hepatocyte couplets. Am J Physiol 1989; 256: 826–32

    Google Scholar 

  48. Weinman S, Carruth M, Dawson P. Bile acid uptake via the human apical sodium-bile acid cotransporter is electrogenic. J Biol Chem 1998; 273: 34691–5

    Article  PubMed  CAS  Google Scholar 

  49. Smith P, Pritchard J, Miller D. Membrane potential drives organic cation transport into teleost renal proximal tubules. Am J Physiol 1988; 255: 492–9

    Google Scholar 

  50. Luxon B, Weisiger R. A new method for quantitating intracellular transport: application to the thyroid hormone 3,5,3′-triiodothyronine. Am J Physiol 1992; 263: 733–41

    Google Scholar 

  51. Luxon BA, Weisiger RA. Sex differences in intracellular fatty acid transport: role of cytoplasmic binding proteins. Am J Physiol 1993; 265: 831–41

    Google Scholar 

  52. Weiss M. Cytoplasmic binding and disposition kinetics of diclofenac in the isolated perfused rat liver. Br J Pharmacol 2000; 130(6): 1331–8

    Article  PubMed  CAS  Google Scholar 

  53. Schwab AJ. Transfer of enalaprilat across rat liver cell membranes is barrier limited. Am J Physiol 1990; 258(3 Pt 1): G461–75

    PubMed  CAS  Google Scholar 

  54. Zucker S, Goessling W, Gollan J. Intracellular transport of small hydrophobic compounds by the hepatocyte. Semin Liv Dis 1996; 16: 159–67

    Article  CAS  Google Scholar 

  55. Stolz A. The role of cytoplasmic proteins in hepatic bile acid transport. Annu Rev Physiol 1989; 51: 161–76

    Article  PubMed  CAS  Google Scholar 

  56. Erlinger S. Do intracellular organelles have any role in transport of bile acids by hepatocytes. J Hepatol 1996; 24 Suppl. 1: 88–93

    Article  PubMed  CAS  Google Scholar 

  57. Gregory D. Mechanism of secretion of biliary lipids: role of a microtubular system in hepatocellular transport of biliary lipids in the rat. Gastroenterology 1978; 74: 93–100

    PubMed  CAS  Google Scholar 

  58. El-Seaidy A, Mills CO, Elias E, et al. Lack of evidence for vesicle trafficking of fluorescent bile salts in rat hepatocyte couplets. Am J Physiol 1997; 272: 298–309

    Google Scholar 

  59. Ishizaki J. Uptake of imipramine in rat liver lysosomes in vitro and its inhibition by basic drugs. J Pharmacol Exp Ther 2000; 294(3): 1088–98

    PubMed  CAS  Google Scholar 

  60. Daniel W, Wojcikowski J. Contribution of lysosomal trapping to the total tissue uptake of psychotropic drugs. Pharmacol Toxicol 1997; 80(2): 62–8

    Article  PubMed  CAS  Google Scholar 

  61. Hung DY. Structure-hepatic disposition relationships for cationic drugs in isolated perfused rat livers: transmembrane exchange and cytoplasmic binding process. J Pharmacol Exp Ther 2001; 297(2): 780–9

    PubMed  CAS  Google Scholar 

  62. Hung D. Cationic drug pharmacokinetics in diseased livers determined by fibrosis index, hepatic protein content, microsomal activity and nature of drug. J Pharmacol Exp Ther 2002; 301(3): 1079–87

    Article  PubMed  CAS  Google Scholar 

  63. Jakoby WB. Detoxication: conjugation and hydrolysis. In: Arias IM, Boyer JL, Fausto N, et al., editors. Liver biology and pathobiology. New York: Raven Press, 1994: 429–42

    Google Scholar 

  64. Horkovics-Kovats S. Efficiency of enterohepatic circulation, its determination and influence on drug bioavailability. Drug Res 1999; 49: 805–15

    CAS  Google Scholar 

  65. Caldwell J. Biological implications of xenobiotic metabolism. In: Arias IM, Jakoby WB, Popper H, editors. The liver: biology and pathobiology. New York: Raven Press, 1988: 355–62.

    Google Scholar 

  66. Mulder GJ, Meerman JHN. The role of extrahepatic and hepatic sulfation and glucuronidation in chemical carcinogenesis: an overview. In: Rydstrom J, Montelius J, Bengtsson M, editors. Extrahepatic drug metabolism and chemical carcinogenesis. Amsterdam: Elsevier Science, 1983: 227–8

    Google Scholar 

  67. Hussain MD. Mechanisms of time-dependent kinetics of diltiazem in the isolated perfused rat liver. Drug Metab Dispos 1993; 22: 36–42

    Google Scholar 

  68. Seitz S, Boelsterli UA. Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats. Gastroenterology 1998; 115: 1476–82

    Article  PubMed  CAS  Google Scholar 

  69. Masimirembwa CM, Otter C, Berg M, et al. Heterologous expression and kinetic characterization of human cytochromes P-450: validation of a pharmaceutical tool for drug metabolism research. Drug Metab Dispos 1999; 27(10): 1117–22

    PubMed  CAS  Google Scholar 

  70. de Wildt SN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet 1999; 37(6): 485–505

    Article  PubMed  Google Scholar 

  71. de Wildt SN. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet 1999; 36(6): 439–52

    Article  PubMed  Google Scholar 

  72. Ballinger LN, Cross SE, Roberts MS. Availability and mean transit times of phenol and its metabolites in the isolated perfused rat liver: normal and retrograde studies using tracer concentrations of phenol. J Pharm Pharmacol 1995; 47(11): 949–56

    Article  PubMed  CAS  Google Scholar 

  73. Evans AM. Membrane transport as a determinant of the hepatic elimination of drugs and metabolites. Clin Exp Pharmacol Physiol 1996; 23(10–11): 970–4

    Article  PubMed  CAS  Google Scholar 

  74. Oinonen T, Lindros K. Zonation of hepatic cytochrome P-450 expression and regulation. Biochem J 1998; 329: 17–35

    PubMed  CAS  Google Scholar 

  75. Palmer C. Localization of cytochrome P-450 gene expression in normal and diseased human liver by in situ hybridization of wax-embedded archival material. Hepatology 1992; 16(3): 682–7

    Article  PubMed  CAS  Google Scholar 

  76. McKinnon R, Hall PD, Quattrochi LC, et al. Localization of CYP1A1 and CYP1A2 messenger RNA in normal human liver and in hepatocellular carcinoma by in situ hybridization. Hepatology 1991; 14(5): 848–56

    Article  PubMed  CAS  Google Scholar 

  77. Tsutsumi M. The intralobular distribution of ethanol-inducible P450IIE1 in rat and human liver. Hepatology 1989; 10(4): 437–46

    Article  PubMed  CAS  Google Scholar 

  78. Niemela O. Cytochromes P450 2A6, 2E1, and 3A and production of protein-aldehyde adducts in the liver of patients with alcoholic and non-alcoholic liver diseases. J Hepatol 2000; 33(6): 893–901

    Article  PubMed  CAS  Google Scholar 

  79. Schwab AJ, Pang KS. The multiple indicator-dilution method for the study of enzyme heterogeneity in liver: theoretical basis. Drug Metab Dispos 1999; 27(6): 746–55

    PubMed  CAS  Google Scholar 

  80. Ring JA. Fetal hepatic drug elimination. Pharmacol Ther 1999; 84(3): 429–45

    Article  PubMed  CAS  Google Scholar 

  81. Kakyo M. Immunohistochemical distribution and functional characterization of an organic anion transporting polypeptide 2 (oatp2). FEBS Lett 1999; 445: 343–6

    Article  PubMed  CAS  Google Scholar 

  82. Burger H. Different capacities for amino acid transport in periportal and perivenous hepatocytes isolated by digitonin/collagenase perfusion. Hepatology 1989; 9: 22–8

    Article  PubMed  CAS  Google Scholar 

  83. Kool M. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci U S A 1999; 96: 6914–9

    Article  PubMed  CAS  Google Scholar 

  84. Kwon Y, Morris ME. Membrane transport in hepatic clearance of drugs II: zonal distribution patterns of concentration-dependent transport and elimination processes. Pharm Res 1997; 14: 780–5

    Article  PubMed  CAS  Google Scholar 

  85. Mainwaring G. The distribution of theta-class glutathione S-transferases in the liver and lung of mouse, rat and human. Biochem J 1996; 318: 297–303

    PubMed  CAS  Google Scholar 

  86. Meyer-Wentrup F. Membrane localization of the electrogenic cation transporter rOCT1 in rat liver. Biochem Biophys Res Commun 1998; 248: 673–8

    Article  PubMed  CAS  Google Scholar 

  87. Moseley R, Jarose S, Permoad P. Hepatic Na+-dicarboxylate cotransport: identification, characterization, and acinar localization. Am J Physiol 1992; 263: G871–9

    PubMed  CAS  Google Scholar 

  88. Pang K. Acinar factors in drug processing: protein binding, futile cycling and cosubstrate. Drug Metab Rev 1995; 27: 325–68

    Article  PubMed  CAS  Google Scholar 

  89. Ploemen J. Ethacrynic acid and its glutathione conjugate as inhibitors of glutathione S-transferases. Xenobiotica 1993; 23: 913–23

    Article  PubMed  CAS  Google Scholar 

  90. Ploemen J, Ommen BV, Bladeren PV. Inhibition of rat and human glutathione S-transferase isoenzymes by ethacrynic acid and its glutathione conjugate. Biochem Pharmacol 1990; 40: 1631–5

    Article  PubMed  CAS  Google Scholar 

  91. Ploemen J. Reversible conjugation of ethacrynic acid with glutathione and human glutathione S-transferase P1-1. Cancer Res 1994; 54: 915–9

    PubMed  CAS  Google Scholar 

  92. Redick J, Jakoby W, Baron J. Immunohistochemical localization of glutathione S-transferases in livers of untreated rats. J Biol Chem 1982; 257: 15200–3

    PubMed  CAS  Google Scholar 

  93. Saiki H. Zonal distribution of cysteine uptake in the perfused rat liver. J Biol Chem 1992; 267: 192–6

    PubMed  CAS  Google Scholar 

  94. Sippel H, Lindros K, Oinonen T. Distribution of glutathione S-transferase isoforms in rat liver after induction by naphthoflavone or 3-methylcholanthrene. Pharmacol Toxicol 1996; 79: 80–6

    Article  PubMed  CAS  Google Scholar 

  95. Stieger B. In situ localization of the hepatocyte Na+/taurocholate cotransporting polypeptide in rat liver. Gastroenterology 1994; 107: 1781–7

    PubMed  CAS  Google Scholar 

  96. Tal M. Restricted expression of the erythroid/brain glucose transporter isoform to perivenous hepatocytes in rats: modulation by glucose. J Clin Invest 1990; 86: 986–92

    Article  PubMed  CAS  Google Scholar 

  97. Tan E, Tirona R, Pang K. Lack of zonal uptake of estrone sulfate in enriched periportal and perivenous isolated rat hepatocytes. Drug Metab Dispos 1999; 27: 336–41

    PubMed  CAS  Google Scholar 

  98. Tirona R, Pang K. Bimolecular glutathione conjugation kinetics of ethacrynic acid in rat liver: in vitro and perfusion studies. J Pharmacol Exp Ther 1999; 290: 1230–41

    PubMed  CAS  Google Scholar 

  99. Oinonen T. Growth hormone-regulated periportal expression of CYP2C7 in the liver. Biochem Pharmacol 2000; 59(5): 583–9

    Article  PubMed  CAS  Google Scholar 

  100. Saarikoski S. Induction of UDP-glycosyltransferase family 1 genes in rat liver: different patterns of mRNA expression with two inducers, 3-methylcholanthrene and beta-naphthoflavone. Biochem Pharmacol 1998; 56(5): 569–75

    Article  PubMed  CAS  Google Scholar 

  101. Gumucio J, Miller D. Functional implications of liver cell heterogeneity. Gastroenterology 1981; 80(2): 393–403

    PubMed  CAS  Google Scholar 

  102. Lecureur V. Expression and regulation of hepatic drug and bile acid transporters. Toxicology 2000; 153(1–3): 203–19

    Article  PubMed  CAS  Google Scholar 

  103. Tirona R. Uptake and glutathione conjugation of ethacrynic acid and efflux of the glutathione adduct by periportal and perivenous rat hepatocytes. J Pharmacol Exp Ther 1999; 291(3): 1210–9

    PubMed  CAS  Google Scholar 

  104. Kwon Y, Kamath A, Morris M. Inhibitors of P-glycoprotein-mediated daunomycin transport in rat liver canalicular membrane vesicles. J Pharm Sci 1996; 85(9): 935–9

    Article  PubMed  CAS  Google Scholar 

  105. Fardel O. Up-regulation of P-glycoprotein expression in rat liver cells by acute doxorubicin treatment. Eur J Biochem 1997; 246(1): 186–92

    Article  PubMed  CAS  Google Scholar 

  106. Alvaro D. The function of alkaline phosphatase in the liver: regulation of intrahepatic biliary epithelium secretory activities in the rat. Hepatology 2000; 32(2): 174–84

    Article  PubMed  CAS  Google Scholar 

  107. Hirohashi T. ATP-dependent transport of bile salts by rat multi-drug resistance-associated protein 3 (Mrp3). J Biol Chem 2000; 275(4): 2905–10

    Article  PubMed  CAS  Google Scholar 

  108. Milne RW. Comparison of the disposition of hepatically-generated morphine-3-glucuronide and morphine-6-glucuronide in isolated perfused liver from the guinea pig. Pharm Res 1997; 14(8): 1014–8

    Article  PubMed  CAS  Google Scholar 

  109. Muller M, Roelofsen H, Jansen PL. Secretion of organic anions by hepatocytes: involvement of homologues of the multidrug resistance protein. Semin Liver Dis 1996; 16(2): 211–20

    Article  PubMed  CAS  Google Scholar 

  110. Patrick J, Kosoglou T, Stauber KL, et al. Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects. Drug Metab Dispos 2002; 30(4): 430–7

    Article  PubMed  CAS  Google Scholar 

  111. Mikov M. The metabolism of drugs by the gut flora. Eur J Drug Metab Pharmacokinet 1994; 19(3): 201–7

    Article  PubMed  CAS  Google Scholar 

  112. Hughes RD, Millburn P, Williams RT. Molecular weight as a factor in the excretion of monoquaternary ammonium cations in the bile of the rat, rabbit and guinea pig. Biochem J 1973; 136: 967–78

    PubMed  CAS  Google Scholar 

  113. Levine W. Biliary excretion of drugs and other xenobiotics. Ann Rev Pharmacol Toxicol 1978; 18: 81–96

    Article  CAS  Google Scholar 

  114. Freedman M, Somberg J. Pharmacology and pharmacokinetics of amiodarone. J Clin Pharmacol 1991; 31(11): 1061–9

    PubMed  CAS  Google Scholar 

  115. Vree T, Timmer C. Enterohepatic cycling and pharmacokinetics of oestradiol in postmenopausal women. J Pharm Pharmacol 1998; 50(8): 857–64

    Article  PubMed  CAS  Google Scholar 

  116. Morris D. Biliary pharmacokinetics of sulbactam plus ampicillin in humans. Rev Infect Dis 1986; 8: 589–92

    Article  Google Scholar 

  117. Carey MC, Duane WC. Enterohepatic circulation. In: Arias IM, Boyer JL, Fausto N, et al., editors. Liver biology and pathobiology. New York: Raven Press, 1994: 719–67

    Google Scholar 

  118. Rollins D, Klaassen C. Biliary excretion of drugs in man. Clin Pharmacokinet 1979; 4(5): 368–79

    Article  PubMed  CAS  Google Scholar 

  119. Zhang R. A mathematical model of the kinetics and tissue distribution of 2-fluoro-beta-alanine, the major catabolite of 5-fluorouracil. Biochem Pharmacol 1993; 45(10): 2063–9

    Article  PubMed  CAS  Google Scholar 

  120. Brown WR, Grodsky GM, Carbone JV. Intracellular distribution of tritiated bilirubin during hepatic uptake and excretion. Am J Physiol 1964; 159: 23–7

    Google Scholar 

  121. Watkins JB, Dykstra TP. Alteration in biliary excretory function by streptozotocin-induced diabetes. Drug Metab Dispos 1987; 15: 177–83

    PubMed  CAS  Google Scholar 

  122. Crosignani A. Clinical pharmacokinetics of therapeutic bile acids. Clin Pharmacokinet 1996; 30: 333–58

    Article  PubMed  CAS  Google Scholar 

  123. Davis T. Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and australian aborigines with type 2 diabetes. Br J Clin Pharmacol 2000; 49: 223–30

    Article  PubMed  CAS  Google Scholar 

  124. Westphal J, Jehl F, Adloff M, et al. Role of intrahepatic protein binding in the hepatobiliary extraction profile of cefixime in humans. Clin Pharmacol Ther 1993; 54(5): 476–84

    Article  PubMed  CAS  Google Scholar 

  125. Dobrinska M. Enterohepatic circulation of drugs. J Clin Pharmacol 1989; 29: 577–80

    PubMed  CAS  Google Scholar 

  126. Strandgarden K. Absorption and disposition including enterohepatic circulation of [14C]roquinimex after oral administration to healthy volunteers. Biopharm Drug Dispos 2000; 21(2): 53–67

    Article  PubMed  CAS  Google Scholar 

  127. Brogden RN, Ward A. Ceftriaxone: a reappraisal of its antibacterial activity and pharmacokinetic properties, and an update on its therapeutic use with particular reference on once-daily administration. Drugs 1988; 35: 604–45

    Article  PubMed  CAS  Google Scholar 

  128. Walstad R. Pharmacokinetics of ceftazidime in patients with biliary tract disease. Eur J Clin Pharmacol 1986; 31(3): 327–31

    Article  PubMed  CAS  Google Scholar 

  129. Kuhn J. Pharmacology of irinotecan. Oncology (Huntingt) 1998; 12(8): 39–42

    CAS  Google Scholar 

  130. Chaudhary A. Multiple-dose lorazapam kinetics: shuttling of lorazepam glucuronide between the circulation and the gut during day- and night-time dosing intervals in response to feeding. J Pharmacol Exp Ther 1992; 267: 1034–8

    Google Scholar 

  131. Sorgel F. Hepatobiliary elimination of temafloxacin. Clin Pharmacokinet 1992; 22: 33–42

    Article  PubMed  Google Scholar 

  132. Barriere SL, Flaherty JF. Third-generation cephalosporins: a critical evaluation. Clin Pharm 1984; 3: 351–73

    PubMed  CAS  Google Scholar 

  133. Zeuzem S. Gut-liver axis. Int J Colorectal Dis 2000; 15(2): 59–82

    Article  PubMed  CAS  Google Scholar 

  134. Pentikainen P. Pharmacokinetics of tolfenamic acid: disposition in bile, blood and urine after intravenous administration to man. Eur J Clin Pharmacol 1984; 27(3): 349–54

    Article  PubMed  CAS  Google Scholar 

  135. Shipkova M, Armstrong VW, Kuypers D, et al. Effect of cyclosporine withdrawal on mycophenolic acid pharmacokinetics in kidney transplant recipients with deteriorating renal function: preliminary report. Ther Drug Monit 2001; 23(6): 717–21

    Article  PubMed  CAS  Google Scholar 

  136. Taras T. Clinical pharmacokinetics of toremifene. Clin Pharmacokinet 2000; 39(5): 327–34

    Article  PubMed  CAS  Google Scholar 

  137. Schmidt L. The effect of selective bowel decontamination on the pharmacokinetics of mycophenolate mofetil in liver transplant recipients. Liver Transpl 2001; 7(8): 739–42

    Article  PubMed  CAS  Google Scholar 

  138. Johnson A. The kinetic of mycophenolic acid and its glucuronide metabolite in adult kidney transplant recipients. Clin Pharmacol Ther 1999; 66: 492–500

    Article  PubMed  CAS  Google Scholar 

  139. Young M, Lettis S, Eastmond R. Concomitant administration of cholestyramine influences the absorption of troglitazone. Br J Clin Pharmacol 1998; 45: 37–40

    Article  PubMed  CAS  Google Scholar 

  140. O’Dwyer P. Pharmacokinetics of the chemopreventive agent oltipraz and of its metabolite M3 in human subjects after a single oral dose. Clin Cancer Res 2000; 6(12): 4692–6

    PubMed  Google Scholar 

  141. Frimmer M, Ziegler K. The transport of bile acids in liver cells. Biochim Biophys Acta 1988; 947: 75–99

    Article  PubMed  CAS  Google Scholar 

  142. Meier PJ. Transport polarity of hepatocytes. Semin Liver Dis 1988; 8: 293–307

    Article  PubMed  CAS  Google Scholar 

  143. Meijer DKF. Current concepts on hepatic transport of drugs. Hepatology 1987; 4: 259–68

    Article  CAS  Google Scholar 

  144. Anwer MS, Hegner D. Effect of Na+ on bile acid uptake by isolated rat hepatocytes. Hoppe-Seylers Z Physiol Chem 1978; 359: 181–92

    PubMed  CAS  Google Scholar 

  145. Stravitz RT. Induction of sodium-dependent bile acid transporter messenger RNA, protein, and activity in rat ileum by cholic acid. Gastroenterology 1997; 113: 1599–608

    Article  PubMed  CAS  Google Scholar 

  146. Anwer MS. Influence of side-chain charge on hepatic transport of bile acids and bile acid analogues. Am J Physiol 1985; 249: 479–88

    Google Scholar 

  147. Aldini R. Hepatic bile acid uptake: effect of conjugation, hydroxyl and ketogroups, and albumin binding. J Lipid Res 1982; 23: 1167–73

    PubMed  CAS  Google Scholar 

  148. Roda A. Quantitative aspects of the interaction of bile acids with human serum albumin. J Lipid Res 1982; 23: 490–5

    PubMed  CAS  Google Scholar 

  149. Iga T, Klaassen CD. Hepatic extraction of bile acids in rats. Biochem Pharmacol 1982; 31: 205–9

    Article  PubMed  CAS  Google Scholar 

  150. O’Maille ER, Richards TG, Short AH. The influence of conjugation of cholic acid on its uptake and secretion: hepatic extraction of taurocholate and cholate in the dog. J Physiol 1987; 189: 337–50

    Google Scholar 

  151. Hoffman NE, Isler JH, Smallwood RA. Hepatic bile acid transport: effect of conjugation and position of hydroxyl groups. Am J Physiol 1975; 229: 298–302

    PubMed  CAS  Google Scholar 

  152. Aldini R. Uptake of bile acids by perfused rat liver: evidence of a structure-activity relationship. Hepatology 1989; 10: 840–5

    Article  PubMed  CAS  Google Scholar 

  153. Dyke RWV, Stephens JE, Scharschmidt BF. Bile acid transport in cultured rat hepatocytes. Am J Physiol 1982; 243: 484–92

    Google Scholar 

  154. Habig WH. The identity of glutathione S-transferase B with ligandin, a major binding protein of liver. Proc Natl Acad Sci U S A 1974; 71: 3879–82

    Article  PubMed  CAS  Google Scholar 

  155. Levi A, Gatmaitan Z, Arias IM. Two hepatic cytoplasmic fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein, and other anions. J Clin Invest 1969; 48: 2156–67

    Article  PubMed  CAS  Google Scholar 

  156. Mishkin S, Stein L, Gatmaitan Z. The binding of fatty acids to cytoplasmic proteins: binding to Z protein in liver and other tissues of the rat. Biochem Biophys Res Commun 1972; 47: 997–1003

    Article  PubMed  CAS  Google Scholar 

  157. Hansen P, Thiesen H, Brodersen R. Bilirubin activity: titrimetric and 13C NMR studies. Acta Chem Scand 1979; 33: 281–93

    Article  CAS  Google Scholar 

  158. Brodersen R. Bilirubin: solubility and interaction with albumin and phospholipid. J Biol Chem 1979; 254: 2364–9

    PubMed  CAS  Google Scholar 

  159. Bonnet R, Davies J, Hursthouse M. Structure of bilirubin. Nature 1976; 262: 326–8

    Article  Google Scholar 

  160. Paumgartner G, Reichen J. Kinetics of hepatic uptake of unconjugated bilirubin. Clin Sci Mol Med 1976; 51: 169–76

    PubMed  CAS  Google Scholar 

  161. Inoue M. Metabolism and transport of amphiphatic molecules in analbuminemic rats and human subjects. Hepatology 1985; 5: 892–8

    Article  PubMed  CAS  Google Scholar 

  162. Stremmel W. Physicochemical and immunohistological studies of a sulfobromophthalein- and bilirubin-binding protein from rat liverplasma membranes. J Clin Invest 1983; 71: 796–805

    Article  Google Scholar 

  163. Stremmel W, Berk PD. Hepatocellular uptake of sulfobromophthalein and bilirubin is selectively inhibited by an antibody to the liver plasma membrane sulfobromophthalein/-bilirubin binding protein. J Clin Invest 1986; 78: 822–6

    Article  PubMed  CAS  Google Scholar 

  164. Scharschmidt BF, Waggoner JG, Berk PD. Hepatic inorganic anion uptake in the rat. J Clin Invest 1975; 56: 1280–92

    Article  PubMed  CAS  Google Scholar 

  165. Hunton DB, Bollman JL, Hoffman HN. The plasma removal of indocyanine green and sulfobromophthalein: II. effect of dosage and blocking agents. J Clin Invest 1961; 40: 1648–55

    Article  PubMed  CAS  Google Scholar 

  166. Goresky CA. Bilirubin and sulfobromophthalein uptake by the liver [abstract]. Gastroenterology 1971; 60: 194

    Google Scholar 

  167. Berk PD, Potter BJ, Stremmel W. Role of plasma membrane ligand-binding proteins in the hepatocellular uptake of albumin-bound organic anions. Hepatology 1987; 7: 165–76

    Article  PubMed  CAS  Google Scholar 

  168. Litwack G, Ketterer B, Arias IM. A hepatic protein which binds steroids, bilirubin, carcinogens, and a number of exogenous anions. Nature 1971; 234: 466–7

    Article  PubMed  CAS  Google Scholar 

  169. Davies N, Skjodt N. Choosing the right nonsteroidal anti-inflammatory drug for the right patient: a pharmacokinetic approach. Clin Pharmacokinet 2000; 38(5): 377–92

    Article  PubMed  CAS  Google Scholar 

  170. Jarvis M. Clinical pharmacokinetics of tricyclic antidepressant overdose. Psychopharmacol Bull 1991; 27(4): 541–50

    PubMed  CAS  Google Scholar 

  171. Kumar R. Vitamin D metabolism and mechanisms of calcium transport. J Am Soc Nephrol 1990; 1(1): 30–42

    PubMed  CAS  Google Scholar 

  172. Weiner IM. Organic acids and bases and uric acid. In: Seldin DW, Giebisch GL, editors. The kidney, physiology and pathophysiology. New York: Raven Press, 1985: 1703–24

    Google Scholar 

  173. Lauterbach F. Intestinal secretion of organic ions and drugs. In: Kramer M, editor. Intestinal permeation. Amsterdam: Excerpta Medica, 1977: 173–95

    Google Scholar 

  174. Suzuki H. Transport of cimetidine by the rat choroid plexus in vitro. J Pharmacol Exp Ther 1986; 239: 927–35

    PubMed  CAS  Google Scholar 

  175. Meijer DKF. Carrier-mediated transport of drugs in the hepatic distribution and elimination of drug, with special reference to the category of organic cations. J Pharmacokinet Biopharm 1990; 18: 35–70

    PubMed  CAS  Google Scholar 

  176. Neef C, Meijer DKF. Structure-pharmacokinetics relationship of quaternary ammonium compounds: correlation of physicochemical and pharmacokinetic parameters. Naunyn Schmiedebergs Arch Pharmacol 1984; 328: 111–8

    Article  PubMed  CAS  Google Scholar 

  177. Feitsma KG. Unequal disposition of enantiomers of the organic cation oxyphenonium in the rat isolated perfused liver. J Pharm Pharmacol 1989; 41: 27–31

    Article  PubMed  CAS  Google Scholar 

  178. Neef C, Oosting R, Meijer DKF. Structure-pharmacokinetics relationship of quaternary ammonium compounds: elimination and distribution characteristics. Naunyn Schmiedebergs Arch Pharmacol 1984; 328: 103–10

    Article  PubMed  CAS  Google Scholar 

  179. Hughes RD, Millburn P, Williams RT. Biliary excretion of some diquaternary ammonium cations in the rat, guinea pig and rabbit. Biochem J 1973; 136: 979–84

    PubMed  CAS  Google Scholar 

  180. Meijer DKF, Weitering JG, Vonk RJ. Hepatic uptake and biliary excretion of d-tubocurarine and trimethylcurarine in the rat in vivo and in isolated perfused rat livers. J Pharmacol Exp Ther 1976; 198: 229–39

    PubMed  CAS  Google Scholar 

  181. Weitering JG. On the localization of d-tubocurarine in rat liver lysosomes in vivo by electron microscopy and subcellular fractionation. Naunyn-Schmiedebergs Arch Pharmacol 1975; 289: 251–6

    Article  PubMed  CAS  Google Scholar 

  182. Westra P. Mechanisms underlaying the prolonged duration of action of muscle relaxants caused by extrahepatic cholestasis. Br J Anaesth 1981; 58: 217–27

    Article  Google Scholar 

  183. Dunkerly R. Gastric and biliary excretion of meperidine in man. Clin Pharmacol Ther 1977; 20: 546–51

    Google Scholar 

  184. Sandberg AA, Slaunwhite WR. Studies on phenolic steroids in human subjects: II. the metabolic fate and hepato-biliary-enteric circulation of 14C-estrone and 14C-estradiol in women. J Clin Invest 1957; 36: 1266–78

    Article  PubMed  CAS  Google Scholar 

  185. Sandberg AA, Slaunwhite WR. Studies on phenolic steroids in human subjects: VII. metabolic fate of estriol and its glucuronide. J Clin Invest 1965; 44: 694–702

    Article  PubMed  CAS  Google Scholar 

  186. Peterson RE. The physiological disposition and metabolic fate of hydrocortisone in man. J Clin Invest 1955; 34: 1779–94

    Article  PubMed  CAS  Google Scholar 

  187. Sandberg AA, Slaunwhite WR. Metabolism of 4-14C-testosterone in human subjects: I. Distribution in bile, blood, faeces and urine. J Clin Invest 1956; 35: 1331–9

    Article  PubMed  CAS  Google Scholar 

  188. Adlercreutz H. Biliary excretion and intestinal metabolism of progesterone and estrogens in man. J Steroid Biochem 1980; 13: 231–44

    Article  PubMed  CAS  Google Scholar 

  189. Ballatori N, Clarkson TW. Biliary secretion of glutathione and of glutathione-metal complexes. Fundam Appl Toxicol 1985; 5: 816–31

    Article  PubMed  CAS  Google Scholar 

  190. Alexander J, Aaseth J, Mikalsen A. Excretion of lead in rat bile — the role of glutathione. Acta Pharmacol Toxicol 1986; 59(7): 486–9

    CAS  Google Scholar 

  191. Gregus Z, Varga F. Role of glutathione and hepatic glutathione S-transferase in the biliary excretion of methyl mercury, cadmium and zinc: a study with enzyme inducers and glutathione depletors. Acta Pharmacol Toxicol 1985; 56: 398–403

    Article  CAS  Google Scholar 

  192. Norseth T. Biliary excretion of chromium in the rat: a role of glutathione. Acta Pharmacol Toxicol 1982; 51: 450–5

    Article  CAS  Google Scholar 

  193. Chipman JK. Bile as a source of potential reactive metabolites. Toxicology 1982; 25: 99–111

    Article  PubMed  CAS  Google Scholar 

  194. Xiong H. Altered hepatobiliary disposition of acetaminophen glucuronide in isolated perfused livers from multidrug resistance-associated protein 2-deficient TR (-) rats. J Pharmacol Exp Ther 2000; 295(2): 512–8

    PubMed  CAS  Google Scholar 

  195. Oude-Elferink R. Hepatobiliary secretion of organic compounds: molecular mechanisms of membrane transport. Biochim Biophys Acta (Rev Biomembr) 1995; 1241: 215–68

    Article  Google Scholar 

  196. Keppler D, Konig J. Expression and localization of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver. FASEB J 1997; 11: 509–16

    PubMed  CAS  Google Scholar 

  197. Kato Y, Igarashi T, Sugiyama Y. Both cMOAT/MRP2 and another unknown transporter(s) are responsible for the biliary excretion of glucuronide conjugate of the nonpeptide angiotensin II antagonist, telmisartan. Drug Metab Dispos 2000; 28(10): 1146–8

    PubMed  CAS  Google Scholar 

  198. Madon J. Functional expression of the rat liver canalicular isoform of the multidrug resistance-associated protein. FEBS Lett 1997; 406: 75–8

    Article  PubMed  CAS  Google Scholar 

  199. Niinuma K. Primary active transport of organic anions on bile canalicular membrane in humans. Am J Physiol 1999; 276(5 Pt 1): G1153–64

    PubMed  CAS  Google Scholar 

  200. Greenberger NJ, Thomas FB. Biliary excretion of 3H-digitoxin: modification by bile salts and phenobarbital. J Lab Clin Med 1973; 81: 241–51

    PubMed  CAS  Google Scholar 

  201. Goresky CA. The enhancement of maximal bilirubin excretion with taurocholate-induced increments in bile flow. Can J Physiol Pharmacol 1974; 52: 389–403

    Article  PubMed  CAS  Google Scholar 

  202. Gregus Z, Fischer E, Varga F. Effect of cholestyramine-induced bile acid depletion on the hepatobiliary transport of cholephilic organic anions in rats. Arch Int Pharmacodyn Ther 1980; 245: 311–22

    PubMed  CAS  Google Scholar 

  203. Gregus Z. Comparison of the effects of cholestyramine and aluminium hydroxide on the biliary bile acid excretion in rats: an experimental model for the depletion of bile acids in bile. Acta Biol Med Ger 1980; 39: 705–9

    PubMed  CAS  Google Scholar 

  204. Watkins JB, Noda H. Biliary excretion of organic anions in diabetic rats. J Pharmacol Exp Ther 1986. 239: 467–73

    PubMed  CAS  Google Scholar 

  205. Rozman K. Hexadecane enhances non-biliary, intestinal excretion of stored hexachlorophenol by rats. Toxicology 1982; 24: 107–13

    Article  PubMed  CAS  Google Scholar 

  206. Cohn WJ. Treatment of chlordecone (Kepone) toxicity with cholestyramine. N Engl J Med 1978; 298: 243–8

    Article  PubMed  CAS  Google Scholar 

  207. Cohn WJ. Distribution and excretion of kepone in humans [abstract]. Gastroenterology 1976; 71: 901

    Google Scholar 

  208. Boyland JJ, Egle JL, Guzelian PS. Cholestyramine: use a new therapeutic approach for chlordecone (Kepone) poisoning. Science 1978; 199: 893–5

    Article  Google Scholar 

  209. Guzelian PS. Comparative toxicology of chlordecone (Kepone) in humans and experimental animals. Annu Rev Pharmacol Toxicol 1982; 22: 89–113

    Article  PubMed  CAS  Google Scholar 

  210. Ballhorn L. Cholestyramine enhances fecal elimination of pentachlorophenol in rhesus monkey. Chemospere 1981; 10: 877–88

    Article  CAS  Google Scholar 

  211. Rozman K. The effect of cholestyramine on the disposition of pentachlorophenol in Rhesus monkeys. J Toxicol Environ Health 1982; 10: 277–83

    Article  PubMed  CAS  Google Scholar 

  212. Billiau A, Bosch JVD. The influence of cholestyramine on the intestinal absorption of glycocholic acid. Arch Int Pharmacodyn Ther 1964; 150: 46–51

    PubMed  CAS  Google Scholar 

  213. Siegers CP, Rozman K, Klaassen CD. Biliary excretion and enterohepatic circulation of paracetamol in the rat. Xenobiotica 1983; 13: 591–6

    Article  PubMed  CAS  Google Scholar 

  214. Siegers CP, Moller-Hartmann W. Cholestyramine as an antidote against paracetamol-induced hepato- and nephrotoxicity in the rat. Toxicol Lett 1989; 47: 179–84

    Article  PubMed  CAS  Google Scholar 

  215. Neuvonen PJ, Elonen E. Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. Eur J Clin Pharmacol 1980; 17: 51–7

    Article  PubMed  CAS  Google Scholar 

  216. Elomaa K. The possible role of enterohepatic cycling on bio-availability of norethisterone and gestodene in women using combined oral contraceptives. Contraception 2001; 63(1): 13–8

    Article  PubMed  CAS  Google Scholar 

  217. Heimer GM, Englund DE. Enterohepatic recirculation of oestriol: inhibition by activated charcoal. Acta Endocrinol (Copenh) 1986; 113(1): 93–5

    CAS  Google Scholar 

  218. Gregus Z, Klaasen CD. Enterohepatic circulation of toxicants. In: Rozman K, Hanninen O, editors. Gastrointestinal toxicology. New York: Elsevier, 1986: 57–118

    Google Scholar 

  219. Caldwell J. Comparative aspects of detoxication in mammals. In: Jacoby WB, editor. Enzymatic basis of detoxication. New York: Academic Press, 1980: 85–114

    Google Scholar 

  220. Gregus Z. Hepatic phase I and phase II biotransformation in quail and trout: comparison to other species commonly used in toxicity testing. Toxicol Appl Pharmacol 1983; 67: 430–41

    Article  PubMed  CAS  Google Scholar 

  221. Laitinen M, Watkins III JB. Mucosal biotransformation. In: Rozman K, Hanninen O, editors. Gastrointestinal toxicology. Amsterdam: Elsevier, 1986: 169–92

    Google Scholar 

  222. Scheline RR. Metabolism of foreign compounds by gastrointestinal microorganisms. Pharmacol Rev 1973; 25: 451–523

    PubMed  CAS  Google Scholar 

  223. Drasar BS, Hill MJ. Human intestine flora. New York: Academic Press, 1974

    Google Scholar 

  224. Kararli TT. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm Drug Dispos 1995; 16(5): 351–80

    Article  PubMed  CAS  Google Scholar 

  225. Suchy FJ, Heubi JE, Balistreri WF. The enterohepatic circulation of bile acids in suckling and weandling rats [abstract]. Gastroenterology 1981; 80: 1351

    Google Scholar 

  226. Klaassen CD. Hepatic excretory function in the newborn rat. J Pharmacol Exp Ther 1973; 184: 721–8

    PubMed  CAS  Google Scholar 

  227. Kleeberg U. Effect of 3-methylcholanthrene on the biliary excretion of bromsulphthalein and eosine in newborn rats. Acta Physiol Acad Sci Hung 1979; 53: 363–7

    PubMed  CAS  Google Scholar 

  228. McMahon TF, Beierschmitt WP, Weiner M. Changes in phase I and phase II biotransformation with age in male Fischer 344 rat colon: relationship to colon carcinogenesis. Cancer Lett 1987; 36: 273–82

    Article  PubMed  CAS  Google Scholar 

  229. Greenberger DJ, Engelkling LR. Enterohepatic circulation of lorazepam and acetaminophen conjugates in ponies. J Pharmacol Exp Ther 1988; 244: 674–9

    Google Scholar 

  230. Meuldermans W. Excretion and biotransformation of alfentanil and sufentanil in rats and dogs. Drug Metab Dispos 1987; 15: 905–13

    PubMed  CAS  Google Scholar 

  231. Solymoss B, Zsigmond G. Effects of various steroids on the hepatic glucuronidation and biliary excretion of bilirubin. Can J Physiol Pharmacol 1973; 51: 319–23

    Article  PubMed  CAS  Google Scholar 

  232. Levine WG. The role of the hepatic endoplasmic reticulum in the biliary excretion of foreign compounds by the rat: the effect of phenobarbitone and SKF525-A (diethylaminoethyl diphenyl-propylacetate). Biochem Pharmacol 1970; 19: 235–44

    Article  PubMed  CAS  Google Scholar 

  233. Fawaz F. Influence of poly (DL-lactide) nanocapsules on the biliary clearance and enterohepatic circulation of indomethacin in the rabbit. Pharm Res 1993; 10(5): 750–6

    Article  PubMed  CAS  Google Scholar 

  234. Sabordo L. Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of clofibric acid, acetaminophen, and acetaminophen glucuronide. J Pharmacol Exp Ther 2000; 295(1): 44–50

    PubMed  CAS  Google Scholar 

  235. Kim R, Leake B, Cvetkovic M, et al. Modulation by drugs of human hepatic sodium-dependent bile acid transporter (sodium taurocholate cotransporting polypeptide) activity. J Pharmacol Exp Ther 1999; 291(3): 1204–9

    PubMed  CAS  Google Scholar 

  236. Dantzig A. Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. Curr Med Chem 2001; 8(1): 39–50

    Article  PubMed  CAS  Google Scholar 

  237. Morikawa A. Biliary excretion of 17beta-estradiol 17beta-D-glucuronide is predominantly mediated by cMOAT/MRP2. Pharm Res 2000; 17(5): 546–52

    Article  PubMed  CAS  Google Scholar 

  238. Yam J, Roberts RJ. Hepatic uptake of foreign compounds: influence of acute extrahepatic biliary obstruction. J Pharmacol Exp Ther 1977; 200: 425–33

    PubMed  CAS  Google Scholar 

  239. Klaassen CD. Comparison of the effects of two-thirds hepatectomy and bile-duct ligation on hepatic excretory function. J Pharmacol Exp Ther 1974; 191: 25–31

    PubMed  CAS  Google Scholar 

  240. Siegers CP. Effects of liver injury and cholestasis on microsomal enzyme activities and in vivo metabolism of halothane, enflurane and methoxyflurane. Xenobiotica 1981 11: 293–9

    Article  PubMed  CAS  Google Scholar 

  241. Siegers CP, Klaassen CD. Biliary excretion of acetaminophen in ureter-ligated rats. Pharmacology 1984; 29: 177–80

    Article  Google Scholar 

  242. Kullak-Ublick G, Beuers U, Paumgartner G. Hepatobiliary transport. J Hepatol 2000; 32(1): 3–18

    Article  PubMed  CAS  Google Scholar 

  243. Lindell T. Specific inhibition of nuclear RNA polymerase II by α-amanitin. Science 1970; 170: 447–9

    Article  PubMed  CAS  Google Scholar 

  244. Reichen J. Decreased uptake of taurocholate and ouabain by hepatocytes isolated from cirrhotic rat liver. Hepatology 1987; 7: 67–70

    Article  PubMed  CAS  Google Scholar 

  245. Beuers U. Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis. J Clin Invest 1993; 92: 2984–93

    Article  PubMed  CAS  Google Scholar 

  246. Wood A. Intact hepatocyte theory of impaired drug metabolism in experimental cirrhosis in the rat. Gastroenterology 1979; 76: 1358–62

    PubMed  CAS  Google Scholar 

  247. Varin F, Huet PM. Hepatic microcirculation in the perfused cirrhotic rat liver. J Clin Invest 1991; 76: 1904–12

    Article  Google Scholar 

  248. Sherman I, Pappas S, Fisher M. Hepatic microvascular changes associated with development of liver fibrosis and cirrhosis. Am J Physiol 1990; 258: 460–5

    Google Scholar 

  249. Milani S. Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol 1994; 144: 528–37

    PubMed  CAS  Google Scholar 

  250. Murawaki Y. Serum collagenase activity reflects the amount of liver collagenase in chronic carbon tetrachloride-treated rats. Res Commun Chem Pathol Pharmacol 1994; 84: 63–72

    PubMed  CAS  Google Scholar 

  251. Krähenbühl S, Stucki J, Reichen J. Reduced activity of the electron transport chain in liver mitochondria isolated from rats with secondary biliary cirrhosis. Hepatology 1992; 15: 1160–6

    Article  PubMed  Google Scholar 

  252. Gebhart A, Brabec M. Carbon tetrachloride depresses hepatic phospholipid synthesis in rats. Toxicol Lett 1985; 24: 71–8

    Article  PubMed  CAS  Google Scholar 

  253. Muriel P, Favari L, Soto C. Erythrocyte alterations correlate with CC14 and biliary obstruction-induced liver damage in the rat. Life Sci 1993; 52: 647–55

    Article  PubMed  CAS  Google Scholar 

  254. Yahuaca P. Cryptic adenosine triphosphatase activities in plasma membranes of CC14-cirrhotic rats. Lab Invest 1985; 53: 541–5

    PubMed  CAS  Google Scholar 

  255. Hong S, Chung S, Shim C. Functional impairment of sinusoidal membrane transport of organic cations in rats with CC14-induced hepatic failure. Pharm Res 2000; 17(7): 833–8

    Article  PubMed  CAS  Google Scholar 

  256. Feuer G, Fonzo CD. Intrahepatic cholestasis: a review of biochemical-pathological mechanisms. Drug Metabol Drug Interact 1992; 10: 1–161

    Article  PubMed  CAS  Google Scholar 

  257. Reichen J. Mechanisms of cholestasis. In: Tavoloni N, Berk P, editors. Hepatic transport and bile secretion: physiology and pathophysiology. New York: Raven Press, 1993: 665–72

    Google Scholar 

  258. Schaffner F, Popper H. Classification and mechanism of cholestasis. In: Wright R, editor. Liver and biliary disease: pathophysiology, diagnosis, management. London: WB Saunders Company Ltd, 1979: 296–323

    Google Scholar 

  259. Phillips M, Latham P, Poucell S. Electron microscopy of human liver disease. In: Schiff L, Schiff E, editors. Diseases of the liver. Philadelphia: JB Lippincott Co, 1987: 47–76

    Google Scholar 

  260. Plaa G, Priestly B. Intrahepatic cholestasis induced by drugs and chemicals. Pharmacol Rev 1976; 28: 207–73

    PubMed  CAS  Google Scholar 

  261. Becker B, Plaa G. Quantitative and temporal delineation of various parameters of liver dysfunction due to alpha-naphthylisothiocyanate. Toxicol Appl Pharmacol 1965; 7: 708–18

    Article  PubMed  CAS  Google Scholar 

  262. Indacochea-Redmond N, Plaa G. Functional aspects of alpha-naphthylisothiocyanate in various species. Toxicol Appl Pharmacol 1971; 19: 71–80

    Article  PubMed  CAS  Google Scholar 

  263. Lock S, Lavigne J, Plaa G. The effect of alpha-naphthylisothiocyanate on bile secretion prior to and during the onset of cholestasis in the rat. Toxicol Lett 1982; 10: 427–35

    Article  PubMed  CAS  Google Scholar 

  264. Wieland T. Identity of hepatic membrane transport systems for bile salts, phalloidin, and antamanide by photoaffinity labelling. Proc Natl Acad Sci U S A 1984; 81: 5232–6

    Article  PubMed  CAS  Google Scholar 

  265. Kramer W. Bile-salt-binding polypeptides in plasma membranes of hepatocytes revealed by photoaffmity labelling. Eur JBiochem 1982; 129: 13–24

    Article  CAS  Google Scholar 

  266. Gabbiani G. Phalloidin-induced hyperplasia of actin filaments in rat hepatocytes. Lab Invest 1975; 53: 562–9

    Google Scholar 

  267. Tuchweber B, Gabbiani G. Phalloidin-induced hyperplasia of actin microfilaments in rat hepatocytes. In: Preisig R, Bircher J, Paumgartner G, editors. The liver: quantitative aspects of structure and function. Basel: S Karger AG, 1976: 84–90

    Google Scholar 

  268. Jansen P. The pathophysiology of cholestasis with special reference to primary biliary cirrhosis. Baillieres Best Pract Res Clin Gastroenterol 2000; 14(4): 571–83

    Article  PubMed  CAS  Google Scholar 

  269. Liber M. The incidence of gallstones and their correlation with other diseases. Am Surg 1952; 135: 394–405

    Google Scholar 

  270. Feldman M, Feldman M. The incidence of cholelithiasis, cholesterosis and liver disease in diabetes mellitus: an autopsy study. Diabetes 1954; 3: 3505–9

    Google Scholar 

  271. Goldstein M, Schein C. The significance of biliary tract disease in the diabetic: its unique features. Am J Gastroenterol 1963; 39: 630–4

    PubMed  CAS  Google Scholar 

  272. Grant M, Duthie S. Conjugation reactions in hepatocytes isolated from streptozotocin-induced diabetic rats. Biochem Pharmacol 1987; 36: 3647–55

    Article  PubMed  CAS  Google Scholar 

  273. Salmela P, Sotaniemi E, Pelkonen R. The evaluation of the drug-metabolizing capacity in patients with diabetes mellitus. Diabetes 1980; 29: 788–94

    Article  PubMed  CAS  Google Scholar 

  274. Watkins J, Dykstra T. Alterations in biliary excretory function by streptozotocin-induced diabetes. Drug Metab Dispos 1987; 15: 177–83

    PubMed  CAS  Google Scholar 

  275. Carnovale C, Marinelli R, Rodriguez-Garay E. Bile flow decrease and altered bile composition in streptozotocin-treated rats. Biochem Pharmacol 1986; 35: 2625–8

    Article  PubMed  CAS  Google Scholar 

  276. Berk P, Stump D. Mechanisms of cellular uptake of long chain free fatty acids. Mol Cell Biochem 1999; 192: 17–31

    Article  PubMed  CAS  Google Scholar 

  277. Danysz A, Wisniewski K. The influence of insulin on drug passage into the tissues. Arch Int Pharmacodyn Ther 1965; 158: 30–8

    PubMed  CAS  Google Scholar 

  278. Jefferson L. Diabetes induced alterations in liver protein synthesis. J Biol Chem 1983; 258: 1369–75

    PubMed  CAS  Google Scholar 

  279. Huang Z, Murakami T, Okochi A. Expression and function of P-glycoprotein in rats with glycerol-induced acute renal failure. Eur J Pharmacol 2000; 406(3): 453–60

    Article  PubMed  CAS  Google Scholar 

  280. Zollner G, Fickert P, Zenz R. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 2001; 33(3): 633–46

    Article  PubMed  CAS  Google Scholar 

  281. Vree T, Ven AVD. Clinical consequences of the biphasic elimination kinetics for the diuretic effect of furosemide and its acyl glucuronide in humans. J Pharm Pharmacol 1999; 51(3): 239–48

    Article  PubMed  CAS  Google Scholar 

  282. Bullingham R, Nicholls A, Kamm B. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34(6): 429–55

    Article  PubMed  CAS  Google Scholar 

  283. Funaki T. Enterohepatic circulation model for population pharmacokinetic analysis. J Pharm Pharmacol 1999; 10: 1143–8

    Article  Google Scholar 

  284. Shepard T, Reuning R, Aarons L. Interpretation of area under the curve measurements for drugs subject to enterohepatic cycling. J Pharm Sci 1985; 2: 227–8

    Article  Google Scholar 

  285. Shepard T, Gannaway D, Lockwood G. Accumulation and time to steady state for drugs subject to enterohepatic cycling: a stimulation study. J Pharm Sci 1985; 12: 1331–3

    Article  Google Scholar 

  286. Shepard T, Reuning R, Aarons L. Estimation of area under the curve for drugs subject to enterohepatic cycling. J Pharmacokinet Biopharm 1985; 6: 589–608

    Google Scholar 

  287. Dahlstrom B, Paalzow L. Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat. J Pharmacokinet Biopharm 1978; 6: 505–19

    PubMed  CAS  Google Scholar 

  288. Pollack G, Brouwer K. Physiologic and metabolic influences on enterohepatic recirculation: simulations based upon the disposition of valproic acid in the rat. J Pharmacokinet Biopharm 1991; 2: 189–225

    Google Scholar 

  289. Ouellet D, Pollack G. Biliary excretion and enterohepatic recirculation of morphine-3-glucuronide in rats. Drug Metab Dispos 1995; 23: 478–784

    PubMed  CAS  Google Scholar 

  290. Steimer J, Plusquellec Y, Guillaume A, et al. A time-lag model for pharmacokinetics of drugs subject to enterohepatic circulation. J Pharm Sci 1982; 3: 297–302

    Article  Google Scholar 

  291. Peris-Ribera J, Kanba M, Toyoda Y, et al. General treatment of the enterohepatic recirculation of drugs and its influence on the area under the plasma level curves, bioavailability, and clearance. Pharm Res 1992; 10: 1306–13

    Article  Google Scholar 

  292. Wang Y, Reuning R. An experimental design strategy for quantitating complex pharmacokinetic models: enterohepatic circulation with time-varying gallbladder emptying as an example. Pharm Res 1992; 2: 169–77

    Article  Google Scholar 

  293. Colburn W, Lucek R. Noncompartmental area under the curve determinations for drugs that cycle in the bile. Biopharm Drug Dispos 1988; 9(5): 465–75

    Article  PubMed  CAS  Google Scholar 

  294. Semmes R, Shen D. A reversible clearance model for the enterohepatic circulation of drug and conjugate metabolite pair. Drug Metab Dispos 1990; 18(1): 80–7

    PubMed  CAS  Google Scholar 

  295. Veng-Pedersen P, Miller R. Pharmacokinetics of doxycycline reabsorption. J Pharm Sci 1980; 69: 204–398

    Article  Google Scholar 

  296. Plusquellec Y, Houin G. Drug recirculation model with multiple cycles occurring at unequal time intervals. J Biomed Eng 1992; 6: 521–6

    Article  Google Scholar 

  297. Plusquellec Y, Arnaud R, Saivin S, et al. Enterohepatic recirculation of the new antihypertensive drug UP 269-6 in humans: a possible model to account for multiple plasma peaks. Arzneimittel Forschung 1998; 48: 138–44

    PubMed  CAS  Google Scholar 

  298. Shepard T. Mean residence time for drugs subject to enterohepatic cycling. J Pharmacokinet Biopharm 1989; 3: 327–45

    Google Scholar 

  299. Yamaoka K, Kanba M, Toyoda Y, et al. Analysis of enterohepatic circulation of cefixime in rat by fast inverse Laplace transform (FILT). J Pharmacokinet Biopharm 1990; 6: 545–59

    Google Scholar 

  300. Yamaoka K. Disposition analysis by fast inverse Laplace transform. Yakugaku Zasshi 1992; 112(8): 503–15

    PubMed  CAS  Google Scholar 

  301. Yasui H, Yamaoka K, Nakagawa T. Moment analysis of stereoselective enterohepatic circulation and unidirectional chiral inversion of ketoprofen enantiomers in rat. J Pharm Sci 1996; 85: 580–5

    Article  PubMed  CAS  Google Scholar 

  302. Fukuyama T. A new analysis method for disposition kinetics of enterohepatic circulation of diclofenac in rats. Drug Metab Dispos 1994; 22: 479–85

    PubMed  CAS  Google Scholar 

  303. Ploeger B, Mesinga T, Sips A, et al. A human physiologically-based model for glycyrrhzic acid, a compound subject to pre-systemic metabolism and enterohepatic cycling. Pharm Res 2000; 17(12): 1516–25

    Article  PubMed  CAS  Google Scholar 

  304. Wang Y, Roy A, Sun L, et al. A double-peak phenomenon in the pharmacokinetics of alprazolam after oral administration. Drug Metab Dispos 1999; 27(8): 855–9

    PubMed  CAS  Google Scholar 

  305. Veng-Pedersen P, Miller R. Pharmacokinetics and bioavailability of cimetidine in humans. J Pharm Sci 1980; 69(4): 394–8

    Article  Google Scholar 

  306. Abshagen U. Effect of enterohepatic circulation on the pharmacokinetics of spironolactone in man. Naunyn Schmiedebergs Arch Pharmacol 1977; 300: 281–7

    PubMed  CAS  Google Scholar 

  307. Duggan D. The disposition of sulindac. Clin Pharm Ther 1977; 21: 326–35

    CAS  Google Scholar 

  308. Hoglund P, Ohlin M. Effect modelling for drugs undergoing enterohepatic circulation. Eur J Drug Metab Pharmacokinet 1993; 18(4): 333–8

    Article  PubMed  CAS  Google Scholar 

  309. Serra M, Caballero A, Del Olmo JA, et al. Maximal biliary transport of sulfobromophthalein in patients with a T-tube placed in the common bile duct. Eur J Drug Metab Pharmacokinet 1997; 22(2): 135–9

    Article  PubMed  CAS  Google Scholar 

  310. Fleuren H, Wissen CV-V, Thien T. Biliary excretion of chlorthalidone inhumans. Biopharm Drug Dispos 1980; 1(3): 103–10

    Article  PubMed  CAS  Google Scholar 

  311. Kreek M. Biliary secretion of methadone and methadone metabolites in man. Res Commun Chem Pathol Pharmacol 1980; 29(1): 67–78

    PubMed  CAS  Google Scholar 

  312. Buchan PC, Klopper A. Enterohepatic circulation of oestriol: a study of the effects of ampicillin on plasma oestriol levels. Br J Obstet Gynaecol 1979; 86(9): 713–6

    Article  PubMed  CAS  Google Scholar 

  313. Shenfield GM, Griffin JM. Clinical pharmacokinetics of contraceptive steroids: an update. Clin Pharmacokinet 1991; 20(1): 15–37

    Article  PubMed  CAS  Google Scholar 

  314. Shenfield G. Oral contraceptives: are drug interactions of clinical significance?. Drug Saf 1993; 9(1): 21–37

    Article  PubMed  CAS  Google Scholar 

  315. Weisberg E. Interactions between oral contraceptives and antifungals/antibacterials: is contraceptive failure the result?. Clin Pharmacokinet 1999; 36(5): 309–13

    Article  PubMed  CAS  Google Scholar 

  316. Lin J, Lu A. Interindividual variability in inhibition and induction of cytochrome p450 enzymes. Annu Rev Pharmacol Toxicol 2001; 41: 535–67

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We wish to acknowledge the support of the Australian National Health and Medical Research Council (M.S.R., B.M.M., M.W.), Medical Research Council of Canada Grant No. MT 13683 (F.J.B.), and the Princess Alexandra Hospital Research Foundation (F.J.B.).

Author information

Authors and Affiliations

  1. Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, 4102, Australia

    Michael S. Roberts & Beatrice M. Magnusson

  2. Faculty of Pharmacy and Department of Pharmacology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

    Frank J. Burczynski

  3. Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany

    Michael Weiss

Authors
  1. Michael S. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Beatrice M. Magnusson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank J. Burczynski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael S. Roberts.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Roberts, M.S., Magnusson, B.M., Burczynski, F.J. et al. Enterohepatic Circulation. Clin Pharmacokinet 41, 751–790 (2002). https://doi.org/10.2165/00003088-200241100-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200241100-00005

Keywords

search

Navigation