Skip to main content
SpringerLink
Log in

Physiologic and metabolic influences on enterohepatic recirculation: Simulations based upon the disposition of valproic acid in the rat

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

The potential influence of alterations in several physiologic processes (hepatocellular egress, biliary excretion, gastrointestinal transit) and biotransformation steps (oxidative metabolism, glucuronidation) on the disposition of agents subject to significant enterohepatic recirculation (ER) via the glucuronide conjugate was examined in a series of simulation experiments. The model of ER developed was based upon the disposition of valproic acid (VPA) and valproate glucuronide (VPA-G) in the rat. The systemic disposition of VPA was simulated following changes in several processes contributing to (or competing with) ER: hepatic oxidative metabolism, hepatic glucuronidation, sinusoidal egress of glucuronide conjugate, canalicular egress of glucuronide conjugate, and gastrointestinal transit. Changes in the formation clearance of VPA-G resulted in a less than proportional change in systemic clearance of VPA, whereas changes in oxidative metabolism led to a greater than proportional change in systemic clearance. Furthermore, alterations in hepatocellular egress of VPA-G affected the disposition of the parent compound, suggesting that drug interactions or disease state effects on metabolite transport may be misinterpreted as effects at the level of metabolite formation. Analytical methods are proposed to recover the intrinsic kinetic parameters (formation clearances of metabolites, renal clearance of parent, volume of distribution) in the presence of ER from the systemic disposition of the parent alone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. B. E. Dahlstrom and L. K. Paalzow. Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat.J. Pharmacokin. Biopharm. 6:505–519 (1978).

    Article  CAS  Google Scholar 

  2. J. H. Lin, K. C. Yen, and D. E. Duggan. Effect of enterohepatic circulation on the pharmacokinetics of diflunisal in rats.Drug Metab. Dispos. 13:321–326 (1985).

    CAS  PubMed  Google Scholar 

  3. R. J. Herman, J. D. Van Pham, and C. B. N. Szakacs. Disposition of lorazepam in human beings: Enterohepatic recirculation and first-pass effect.Clin. Pharmacol. Ther. 46:18–25 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. F. L. S. Tse, F. Ballard, and J. Skinn. Estimating the fraction reabsorbed for drugs undergoing enterohepatic circulation.J. Pharmacokin. Biopharm. 10:455–461 (1982).

    Article  CAS  Google Scholar 

  5. R. G. Dickinson, R. C. Harland, A. M. Ilias, R. M. Rodgers, S. N. Kaufman, R. K. Lynn, and N. Gerber. Disposition of valproic acid in the rat: Dose-dependent metabolism, distribution, enterohepatic recirculation, and choleretic effect.J. Pharmacol. Exp. Ther. 211:583–595 (1979).

    CAS  PubMed  Google Scholar 

  6. K. Singh, J. M. Orr, and F. S. Abbott. Pharmacokinetics and enterohepatic circulation of 2-n-propyl-4-pentenoic acid in the rat.Drug Metab. Dispos. 16:848–852 (1988).

    CAS  PubMed  Google Scholar 

  7. O. J. McAnena, M. Rossi, B. M. Mehta, and J. M. Daly. Alteration of methotrexate metabolism in rats by administration of an elemental liquid diet. I. Changes in drug enterohepatic circulation.Cancer 59:31–37 (1987).

    Article  CAS  PubMed  Google Scholar 

  8. K. C. Kwan, G. O. Breault, E. R. Umbenhauer, F. G. McMahon, and D. E. Duggan. Kinetics of indomethacin absorption, elimination, and enterohepatic circulation in man.J. Pharmacokin. Biopharm. 4:255–280 (1976).

    Article  CAS  Google Scholar 

  9. T. R. D. Elmhirst, J. K. Chipman, O. Ribeiro, P. C. Hirom, and P. Millburn. Metabolism and enterohepatic circulation of benzo(a)pyrene-4,5-epoxide in the rat.Xenobiotica 15:899–906 (1985).

    Article  CAS  PubMed  Google Scholar 

  10. H. Kurebayashi, A. Tanaka, and T. Yamaha. Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat.Toxicol. Appl. Pharmacol. 77:395–404 (1985).

    Article  CAS  PubMed  Google Scholar 

  11. D. E. Duggan, K. F. Hooke, R. M. Noll, and K. C. Kwan. Enterohepatic circulation of indomethacin and its role in intestinal irritation.Biochem. Pharmacol. 25:1749–1754 (1975).

    Article  Google Scholar 

  12. R. Gugler and G. E. von Unruh. Clinical pharmacokinetics of valproic acid.Clin. Pharmacokin. 5:67–83 (1980).

    Article  CAS  Google Scholar 

  13. F. Schobben and E. van der Kleijn. Valproate biotransformation. In D. M. Woodbury, J. K. Penry, and C. E. Pippinger (eds.),Antiepileptic Drugs, Raven, New York, 1982, pp. 567–578.

    Google Scholar 

  14. A. Rescigno and G. Segre.Drug and Tracer Kinetics, Blaisdell, Waltham, MA, 1966.

    Google Scholar 

  15. J. Barre, J. M. Chamouard, G. Houin, and J. P. Tillement. Equilibrium dialysis, ultrafiltration, and ultracentrifugation compared for determining the plasma-protein-binding characteristics of valproic acid.Clin. Chem,31:60–64 (1985).

    CAS  PubMed  Google Scholar 

  16. W. Loscher. Rapid determination of valproate sodium in serum by gas-liquid chromatography.Epilepsia 18:782–787 (1978).

    Google Scholar 

  17. W. Loscher and H. Esenwein. Pharmacokinetics of sodium valproate in dog and mouse.Arzneim. Forsch. 28:782–787 (1978).

    CAS  Google Scholar 

  18. H. Akaike. An information criterion.Math. Sci. 14:5–9 (1976).

    Google Scholar 

  19. M. Gibaldi and D. Perrier.Pharmacokinetics, 2nd ed. Marcel Dekker, New York, 1985.

    Google Scholar 

  20. U. Bredberg and L. Paaizow. Pharmacokinetics of methylergometrine in the rat: Evidence for enterohepatic recirculation by a linked-rat model.Pharm. Res. 7:14–20 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. G. M. Pollack. Pharmacokinetic factors contributing to the nonlinear disposition of valproic acid in the rat.Pharm. Res. 3:145 (1986).

    Google Scholar 

  22. G. D. Anderson, A. Acheampong, A. J. Wilensky, and R. H. Levy. Effect of valproate (VPA) dose on formation of hepatotoxic metabolites.Clin. Pharmacol. Ther. 47:130 (1990).

    Article  Google Scholar 

  23. P. veng Pedersen and R. Miller. Pharmacokinetics of doxycycline reabsorption.J. Pharm. Sci. 69:204–207 (1980).

    Article  CAS  PubMed  Google Scholar 

  24. J.-L. Steimer, Y. Plusquellec, A. Guillaume, and J.-F. Boisvieux. A time-lag mode for Pharmacokinetics of drugs subject to enterohepatic circulation.J. Pharm. Sci. 71:297–302 (1982).

    Article  CAS  PubMed  Google Scholar 

  25. Y. Plusquellec and L. Bousquet. Time-delay for two-compartment models used for study of enterohepatic circulation of drugs.IEEE Trans. Biomed. Eng. 6:469–472 (1984).

    Article  Google Scholar 

  26. T. A. Shepard, D. J. Gannaway, and G. F. Lockwood. Accumulation and time to steady state for drugs subject to enterohepatic cycling: A simulation study.J. Pharm. Sci. 74:1331–1333 (1985).

    Article  CAS  PubMed  Google Scholar 

  27. W. A. Colburn. Pharmacokinetic analysis of concentration-time data obtained following administration of drugs that are recycled in the bile.J. Pharm. Sci. 73:313–317 (1984).

    Article  CAS  PubMed  Google Scholar 

  28. J. G. Wagner, A. R. DiSanto, W. R. Gillespie, and K. S. Albert. Reversible metabolism and pharmacokinetics: Application to prednisone-prednisolone.Res. Comm. Chem. Path. Pharmacol. 32:387–405 (1981).

    CAS  Google Scholar 

  29. S. Hwang, K. C. Kwan, and K. S. Albert. A linear model of reversible metabolsim and its application to bioavailability assessment.J. Pharmacokin. Biopharm. 9:693–709 (1981).

    Article  CAS  Google Scholar 

  30. W. F. Ebling and W. J. Jusko. The determination of essential clearance, volume, and residence time parameters of recirculating metabolic systems: The reversible metabolism of methylprednisolone and methylprednisone in rabbits.J. Pharmacokin. Biopharm. 14:557–599 (1986).

    Article  CAS  Google Scholar 

  31. H. Cheng and W. J. Jusko. Mean residence times of multicompartmental drugs undergoing reversible metabolism.Pharm. Res. 7:103–107 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. R. G. Dickinson, R. M. Kluck, M. J. Eadie, and W. D. Hooper. Disposition ofβ- glucuronidase-resistant “glucuronides” of valproic acid after intrabiliary administration in the rat: Intact absorption, fecal excretion, and intestinal hydrolysis.J. Pharmacol. Exp. Ther. 233:214–221 (1985).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pharmaceutics, School of Pharmacy, The University of North Carolina at Chapel Hill, CB #7360, 27599-7360, Chapel Hill, North Carolina

    Gary M. Pollack & Kim L. R. Brouwer

Authors
  1. Gary M. Pollack
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim L. R. Brouwer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pollack, G.M., Brouwer, K.L.R. Physiologic and metabolic influences on enterohepatic recirculation: Simulations based upon the disposition of valproic acid in the rat. Journal of Pharmacokinetics and Biopharmaceutics 19, 189–225 (1991). https://doi.org/10.1007/BF01073869

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01073869

Key words

Search

Navigation