Current Pharmacology Reports

, Volume 3, Issue 5, pp 301–313 | Cite as

Modeling Enterohepatic Circulation

  • Malek Okour
  • Richard C. Brundage
Pharmacometrics (H Kimko, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pharmacometrics


Purpose of Review

The objective of the current analysis is to review the anatomy and physiology of the enterohepatic circulation (EHC); describe how those intricacies affect drug concentration profiles; present various pharmacokinetic models used in the literature to describe EHC concentration-time data; and provide a categorization of these models based on common features.

Recent Findings

The presence of EHC results in longer apparent drug half-lives and the appearance of multiple secondary peaks. Several empirical modeling strategies are present in the literature and these have increased in complexity as our understanding of the impact EHC has on pharmacokinetics, and as the increase in computing power has allowed these models to become more tractable. Although the intent of all these models is to capture the nuances of concentration-time profiles when EHC exists, they remain deficient in their mechanistic representation of the EHC process. In addition, limitations in biological sampling and experimental design present difficulties in our ability to distinguish among some of these models. Finally, the quantitative comparison of different models to literature examples is not possible. Nonetheless, our knowledge of the EHC process and the limitations of our models can be used to inform our interpretation of pharmacokinetic results presented in the literature.


Modeling strategies of EHC vary in the literature. This review article provides a basic review of the EHC process, relates those models to the EHC process, and presents a categorization and summary of modeling strategies implemented to represent EHC.


Enterohepatic Circulation Biliary Pharmacokinetic Modeling 


Compliance with Ethical Standards

Conflict of Interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Supplementary material

40495_2017_96_MOESM1_ESM.docx (20 kb)
ESM 1 (DOCX 19.7 kb)


  1. 1.
    Adlercreutz H, Martin F, Järvenpää P, Fotsis T. Steroid absorption and enterohepatic recycling. Contraception. 1979;20(3):201–23.CrossRefPubMedGoogle Scholar
  2. 2.
    Azezli AD, Bayraktaroglu T, Orhan Y. The use of konjac glucomannan to lower serum thyroid hormones in hyperthyroidism. J Am Coll Nutr. 2007;26(6):663–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Berg AK, Mandrekar SJ, Ziegler KLA, Carlson EC, Szabo E, Ames MM, et al. Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects. J Clin Pharmacol. 2013;53(4):403–12.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet. 1998;34(6):429–55.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen HSG, Gross JF. Pharmacokinetics of drugs subject to enterohepatic circulation. J Pharm Sci. 1979;68(6):792–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Clements M, Chalmers T, Fraser D. Enterohepatic circulation of vitamin D: a reappraisal of the hypothesis. Lancet. 1984;323(8391):1376–9.CrossRefGoogle Scholar
  7. 8.
    Colburn WA. Pharmacokinetic and biopharmaceutic parameters during enterohepatic circulation of drugs. J Pharm Sci. 1982;71(1):131–3.CrossRefPubMedGoogle Scholar
  8. 8.
    Colburn WA, Hirom PC, Parker RJ, Milburn P. A pharmacokinetic model for enterohepatic recirculation in the rat: phenolphthalein, a model drug. Drug Metab Dispos. 1979;7(2):100–2.PubMedGoogle Scholar
  9. 9.
    Dawson PA. Bile Secretion and the Enterohepatic Circulation. In: Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease E-Book: Pathophysiology, Diagnosis, Management, Expert Consult Premium Edition-Enhanced Online Features. Philadelphia: Elsevier Health Sciences; 2010. p. 1075–88.Google Scholar
  10. 10.
    de Winter BC, van Gelder T, Sombogaard F, Shaw LM, van Hest RM, Mathot RA. Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients. J Pharmacokinet Pharmacodyn. 2009;36(6):541.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dibaise JK, Islam RS. Bile acids: an underrecognized and underappreciated cause of chronic diarrhea. Pract Gastroenterol. 2012;36(10):32–44.Google Scholar
  12. 12.
    Dobrinska M. Enterohepatic circulation of drugs. J Clin Pharmacol. 1989;29(7):577–80.CrossRefPubMedGoogle Scholar
  13. 13.
    Drasar BS, Hill MJ. The Distribution of Bacterial Flora in the Intestine In: Drasar BS, Hill MJ, editors. Human intestinal flora. London: Academic Press Ltd; 1974. p. 69–71.Google Scholar
  14. 14.
    Ezzet F, Krishna G, Wexler DB, Statkevich P, Kosoglou T, Batra VK. A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther. 2001;23(6):871–85.CrossRefPubMedGoogle Scholar
  15. 15.
    Fisher RS, Stelzer F, Rock E, Malmud LS. Abnormal gallbladder emptying in patients with gallstones. Dig Dis Sci. 1982;27(11):1019–24.CrossRefPubMedGoogle Scholar
  16. 16.
    Funaki T. Enterohepatic circulation model for population pharmacokinetic analysis. J Pharm Pharmacol. 1999;51(10):1143–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Gao Y, Shao J, Jiang Z, Chen J, Gu S, Yu S, et al. Drug enterohepatic circulation and disposition: constituents of systems pharmacokinetics. Drug Discov Today. 2014;19(3):326-40.CrossRefPubMedGoogle Scholar
  18. 18.
    Hall SD, Thummel KE, Watkins PB, Lown KS, Benet LZ, Paine MF et al. Molecular and physical mechanisms of first-pass extraction. Drug Metab Dispos. 1999;27(2):161–6.Google Scholar
  19. 19.
    Harrison LI, Gibaldi M. Influence of cholestasis on drug elimination: pharmacokinetics. J Pharm Sci. 1976;65(9):1346–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Bertram T, Ludlow J, Basu J. Digestive Trach. In: Haschek WM, Rousseaux CG, Wallig MA, editors. Haschek and Rousseaux's handbook of toxicologic pathology. 3rd ed. New York: Academic Press; 2013. p. 2295.Google Scholar
  21. 21.
    Healey JE, Schroy PC. Anatomy of the biliary ducts within the human liver: analysis of the prevailing pattern of branchings and the major variations of the biliary ducts. AMA Arch Surg. 1953;66(5):599–616.CrossRefPubMedGoogle Scholar
  22. 22.
    Hohenester S, Maillette de Buy Wenniger L, Paulusma CC, van Vliet SJ, Jefferson DM, Oude Elferink RP, et al. A biliary HCO3− umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology. 2012;55(1):173–83.CrossRefPubMedGoogle Scholar
  23. 23.
    Huckle KR, Chipman JK, Hutson DH, Millburn P. Metabolism of 3-phenoxybenzoic acid and the enterohepatorenal disposition of its metabolites in the rat. Drug Metab Dispos. 1981;9(4):360–8.PubMedGoogle Scholar
  24. 24.
    Huntjens D, Strougo A, Chain A, Metcalf A, Summerfield S, Spalding D, et al. Population pharmacokinetic modelling of the enterohepatic recirculation of diclofenac and rofecoxib in rats. Br J Pharmacol. 2008;153(5):1072–84.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ibarra M, Vázquez M, Fagiolino P. Population pharmacokinetic model to analyze nevirapine multiple-peaks profile after a single oral dose. J Pharmacokinet Pharmacodyn. 2014;41(4):363–73.CrossRefPubMedGoogle Scholar
  26. 26.
    Ichikawa T, Ishida S, Sakiya Y, Sawada Y, Hanano M. Biliary excretion and enterohepatic cycling of glycyrrhizin in rats. J Pharm Sci. 1986;75(7):672–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Ide T, Sasaki T, Maeda K, Higuchi S, Sugiyama Y, Ieiri I. Quantitative population pharmacokinetic analysis of pravastatin using an enterohepatic circulation model combined with pharmacogenomic information on SLCO1B1 and ABCC2 polymorphisms. J Clin Pharmacol. 2009;49(11):1309–17.CrossRefPubMedGoogle Scholar
  28. 28.
    Ilett KF, Tee LB, Reeves PT, Minchin RF. Metabolism of drugs and other xenobiotics in the gut lumen and wall. Pharmacol Ther. 1990;46(1):67–93.CrossRefPubMedGoogle Scholar
  29. 29.
    Ings RM. Pharmacokinetics and its application to drug development In: Illing HP, editor. Xenobiotic Metabolism and Disposition: the design of studies on novel compounds. Boca Raton: CRC Press; 1989. p. 120.Google Scholar
  30. 30.
    Jain L, Woo S, Gardner ER, Dahut WL, Kohn EC, Kummar S, et al. Population pharmacokinetic analysis of sorafenib in patients with solid tumours. Br J Clin Pharmacol. 2011;72(2):294–305.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Jiao Z, Jj D, Shen J, Hq L, Lj Z, Wang Y, et al. Population pharmacokinetic modelling for enterohepatic circulation of mycophenolic acid in healthy Chinese and the influence of polymorphisms in UGT1A9. Br J Clin Pharmacol. 2008;65(6):893–907.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Renz JF, Kinkhabwala M. Surgical Anatomy of the Liver. In: Ronald W. Busuttil GBK, editor. Transplantation of the Liver. 3rd ed. Philadelphia: Elsevier Inc; 2013 p. 23–39.Google Scholar
  33. 33.
    Kim TH, Shin S, Landersdorfer CB, Chi YH, Paik SH, Myung J, et al. Population pharmacokinetic modeling of the enterohepatic recirculation of fimasartan in rats, dogs, and humans. AAPS J. 2015;17(5):1210–23.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lecureur V, Courtois A, Payen L, Verhnet L, Guillouzo A, Fardel O. Expression and regulation of hepatic drug and bile acid transporters. Toxicology. 2000;153(1):203–19.CrossRefPubMedGoogle Scholar
  35. 35.
    Lehr T, Staab A, Tillmann C, Trommeshauser D, Schaefer H-G, Kloft C. A Quantitative Enterohepatic Circulation Model. Clin Pharmacokinet. 2009;48(8):529–42.CrossRefPubMedGoogle Scholar
  36. 36.
    Lindner HH, Peña VA, Ruggeri RA. A clinical and anatomical study of anomalous terminations of the common bile duct into the duodenum. Ann Surg. 1976;184(5):626.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Miller R. Pharmacokinetics and bioavailability of ranitidine in humans. J Pharm Sci. 1984;73(10):1376–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Parker R, Hirom P, Millburn P. Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic acid in the rat hydrolysis of glucuronic acid conjugates in the gut lumen. Xenobiotica. 1980;10(9):689–703.CrossRefPubMedGoogle Scholar
  39. 39.
    Philipps AF, Dvorák B, Kling PJ, Grille JG, Koldovský O. Absorption of milk-borne insulin-like growth factor-I into portal blood of suckling rats. J Pediatr Gastroenterol Nutr. 2000;31(2):128–35.CrossRefPubMedGoogle Scholar
  40. 40.
    Plusquellec Y, Houin G. Drug recirculation model with multiple cycles occurring at unequal time intervals. J Biomed Eng. 1992;14(6):521–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Roberts MS, Magnusson BM, Burczynski FJ, Weiss M. Enterohepatic circulation. Clin Pharmacokinet. 2002;41(10):751–90.CrossRefPubMedGoogle Scholar
  42. 42.
    Rosner G, Panetta J, Innocenti F, Ratain M. Pharmacogenetic pathway analysis of irinotecan. Clin Pharmacol Ther. 2008;84(3):393.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Rutkauskas S, Gedrimas V, Pundzius J, Barauskas G, Basevicius A. Clinical and anatomical basis for the classification of the structural parts of liver. Medicina (Kaunas). 2006;42(2):98–106.Google Scholar
  44. 44.
    Sam WJ, Akhlaghi F, Rosenbaum SE. Population pharmacokinetics of mycophenolic acid and its 2 glucuronidated metabolites in kidney transplant recipients. J Clin Pharmacol. 2009;49(2):185–95.CrossRefPubMedGoogle Scholar
  45. 45.
    Shaffer E. Review article: control of gall-bladder motor function. Aliment Pharmacol Ther. 2000;14(s2):2–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Shaffer E, McOrmond P, Duggan H. Quantitative cholescintigraphy: assessment of gallbladder filling and emptying and duodenogastric reflux. Gastroenterology. 1980;79(5 Pt 1):899–906.PubMedGoogle Scholar
  47. 47.
    Shepard TA, Reuning RH, Aarons LJ. Estimation of area under the curve for drugs subject to enterohepatic cycling. J Pharmacokinet Biopharm. 1985a;13(6):589–608.CrossRefPubMedGoogle Scholar
  48. 48.
    Shepard TA, Reuning RH, Aarons LJ. Interpretation of area under the curve measurements for drugs subject to enterohepatic cycling. J Pharm Sci. 1985b;74(2):227–8.CrossRefPubMedGoogle Scholar
  49. 49.
  50. 50.
    Steimer JL, Plusquellec Y, Guillaume A, Boisvieux JF. A time-lag model for pharmacokinetics of drugs subject to enterohepatic circulation. J Pharm Sci. 1982;71(3):297–302.CrossRefPubMedGoogle Scholar
  51. 51.
    Steinberg SE, Campbell CL, Hillman RS. Kinetics of the normal folate enterohepatic cycle. J Clin Investig. 1979;64(1):83.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Strandgården K, Höglund P, Grönquist L, Svensson L, Gunnarsson PO. Absorption and disposition including enterohepatic circulation of (14C) roquinimex after oral administration to healthy volunteers. Biopharm Drug Dispos. 2000;21(2):53–67.CrossRefPubMedGoogle Scholar
  53. 53.
    Takahashi T, May D, Owyang C. Cholinergic dependence of gallbladder response to cholecystokinin in the guinea pig in vivo. Am J Physiol Gastrointest Liver Physiol. 1991;261(4):G565–G9.Google Scholar
  54. 54.
    Toouli J, Bhandari M. Anatomy and physiology of the biliary tree and gallbladder. Diseases of the gallbladder and bile ducts: diagnosis and treatment. 2006:1.Google Scholar
  55. 55.
    Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 1971;231(25):232–5.Google Scholar
  56. 56.
    Veng-Pedersen P, Miller R. Pharmacokinetics and bioavailability of cimetidine in humans. J Pharm Sci. 1980a;69(4):394–8.CrossRefGoogle Scholar
  57. 57.
    Veng-Pedersen P, Miller R. Pharmacokinetics of doxycycline reabsorption. J Pharm Sci. 1980b;69(2):204–7.CrossRefGoogle Scholar
  58. 58.
    Vijayvargiya P, Camilleri M, Shin A, Saenger A. Methods for diagnosis of bile acid malabsorption in clinical practice. Clin Gastroenterol Hepatol. 2013;11(10):1232–9.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Vree TB, André J. 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.CrossRefPubMedGoogle Scholar
  60. 60.
    Wajima T, Yano Y, Oguma T. A pharmacokinetic model for analysis of drug disposition profiles undergoing enterohepatic circulation. J Pharm Pharmacol. 2002;54(7):929–34.CrossRefPubMedGoogle Scholar
  61. 61.
    Watanabe Y, Nagayama M, Okumura A, Amoh Y, Katsube T, Suga T, et al. MR imaging of acute biliary disorders 1. Radiographics. 2007;27(2):477–95.CrossRefPubMedGoogle Scholar
  62. 62.
    Wood M. Eponyms in biliary tract surgery. Am J Surg. 1979;138(6):746–54.CrossRefPubMedGoogle Scholar
  63. 63.
    Yau WP, Vathsala A, Lou HX, Zhou S, Chan E. Mechanism-based enterohepatic circulation model of mycophenolic acid and its glucuronide metabolite: assessment of impact of cyclosporine dose in Asian renal transplant patients. J Clin Pharmacol. 2009;49(6):684–99.CrossRefPubMedGoogle Scholar
  64. 64.
    Younis IR, Malone S, Friedman HS, Schaaf LJ, Petros WP. Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma. Cancer Chemother Pharmacol. 2009;63(3):517–24.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Clinical Pharmacology Modeling and Simulation (CPMS)GlaxoSmithKlineKing of PrussiaUSA
  2. 2.Department of Experimental and Clinical Pharmacology, College of PharmacyUniversity of MinnesotaMinneapolisUSA

Personalised recommendations