Skip to main content
SpringerLink
Log in

Organ Clearance Concepts: New Perspectives on Old Principles

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

Abstract

The removal capacity of an eliminating organ by metabolism and/or excretion is often expressed as its clearance. Metabolic and excretory clearances are considered to be mutually independent, and the sum of these constitute the whole organ clearance. The influence of metabolism on estimates of the excretory clearance and vice versa was examined for the liver and kidney with physiologically based models. Mass transfer first-order rate equations describing transport and removal were derived. Upon inversion of the matrices originating from the coefficients of these equations, the area under the curve (AUC) and clearance (dose/AUC) were obtained with the liver or kidney as the eliminating organ. A more complex solution was found to exist for the kidney since glomerular filtration, secretion; reabsorption. and intrarenal metabolism were present. To ascertain the effect of excretion on estimates of the metabolic clearance as well as the effect of metabolism on estimates of the excretory clearance, intrinsic clearances for excretion or metabolism were set to zero. Clearance values were found to be altered when alternate pathways were present Whereas excretory clearance estimates were consistently reduced in the presence of metabolism, metabolic clearance estimates were affected differentially by excretion and varied according to the site of metabolism. Excretion reduced metabolic clearance estimates when metabolism occurred intracellularly. If metabolism occurred intraluminally (e.g., on the renal brush border or luminal membrane), the metabolic clearance estimate could become higher since the substrate was made available to the enzymes following its excretion. As expected, these changes depended on the relative magnitudes of the intrinsic clearances for metabolism and excretion. The above theory was applied to the elimination of enalapril which is both metabolized and excreted by the perfused rat liver and kidney preparations. Data obtained in these studies were consistent with a set of published physiologic parameters denoting transfer and intrinsic clearances. Perturbations on clearance estimates were studied by setting the metabolic/excretory intrinsic clearance to zero, then to some finite value. In liver, the avid hepatocellular metabolism of enalapril reduced biliary clearance by 73%. For the kidney, the fractional excretion (FE or unbound excretory clearance/glomerular filtration rate) was decreased modestly (from 0.64 to 0.44) with intracellular esterolysis, whereas if metabolism had occurred intraluminally. FE would have been significantly decreased (from 1.8 to 0.45). Simulation results show clearly that clearance estimates are affected by the presence of alternate removal pathways, and question the well-established principle that metabolic and excretory clearance estimates are independent of each other.

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. N. Gréhant. Mesure de l'activite physiologique des reins par le dosage de l'urée dans la sang et dans l'urine. J. Phyisiol. Pathol. Gen. 6:1–8 (1904).

    Google Scholar 

  2. A. E. Lewis. The concept of hepatic clearance. Am. J. Clin. Pathol. 18:789–795 (1948).

    CAS  PubMed  Google Scholar 

  3. G. R. Wilkinson. Clearance approaches in pharmacology. Pharmacol. Rev. 39:1–47 (1987).

    CAS  PubMed  Google Scholar 

  4. K. S. Pang, H. Koster, I. C. M. Halsema, E. Scholtens, G. J. Mulder, and R. N. Stillwell. Normal and retrograde perfusion to probe the zonal distribution of sulfation and glucuronidation activities of harmol in the perfused rat liver preparation. J. Pharmacol. Exp. Ther. 224:647–653 (1983).

    CAS  PubMed  Google Scholar 

  5. H. Koster, I. Halsema, K. S. Pang, E. Scholtens, and G. J. Mulder. Kinetics of sulfation and glucuronidation of harmol in the perfused rat liver preparation. Disappearance of aberrancies in glucuronidation kinetics by inhibition of sulfation. Biochem. Pharmacol. 31:3023–3038 (1982).

    Article  CAS  PubMed  Google Scholar 

  6. M. E. Morris and K. S. Pang. Competition between two enzymes for substrate removal in liver: modulating effects of competitive pathways. J. Pharmacokin. Biopharm. 15:473–496 (1987).

    Article  CAS  Google Scholar 

  7. D. E. Smith and A. R. Kugler. Communications. Influence of intrarenal metabolism on the analysis of renal drug transport mechanisms. J. Pharm. Sci. 83:1519–1520 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. D. E. Smith, A. R. Kugler, and J. B. Schnermann. Reabsorption and metabolism of quinapril and quinaprilat in rat kidney: In vivo micropuncture studies. J. Pharm. Sci. 84:1147–1150 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. A. R. Kluger, S. C. Olson, and D. E. Smith: Disposition of quinapril and quinaprilat in the isolated perfused rat kidney. J. Pharmacokin. Biopharm. 23:287–305 (1995).

    Article  Google Scholar 

  10. B. M. Brenner, L. D. Dworkin, and L. Ichikawa. Glomerular ultrafiltration. In B. M. Brenner and F. C. Rector, Jr. (eds.), The Kidney Third Edition, Philadelphia, 1986, pp. 124–144.

  11. K. B. Bishoff and R. L. Dedrick. Thiopental pharmacokinetics. J. Pharm. Sci. 57:346–1351 (1968).

    Google Scholar 

  12. R. Lutz, R. L. Dedrick, and D. S. Zaharko. Physiological pharmacokinetics: An in vivo approach to membrane transport. Pharmacol. Therm. 11:559–592 (1980).

    Article  CAS  Google Scholar 

  13. I. A. M. de Lannoy, H. Hirayama, and K. S. Pang. A physiological model for renal drug metabolism: enalapril esterolysis to enalaprilat in the isolated perfused rat kidney. J. Pharmacokin. Biopharm. 18:561–588 (1990).

    Article  CAS  Google Scholar 

  14. M. Rowland. The influence of route of administration on drug availability. J. Pharm. Sci. 61:70–74 (1972).

    Article  CAS  PubMed  Google Scholar 

  15. M. Rowland, L. Z. Benet, and G. G. Graham. Clearance concepts in pharmacokinetics. J. Pharmacokin. Biopharm. 1:123–136 (1973).

    Article  CAS  Google Scholar 

  16. P. Hekman and C. A. M. van Ginneken. Kinetic modeling of the renal excretion of iodopyracet in the dog. J. Pharmacokin. Biopharm. 10:77–92 (1982).

    Article  CAS  Google Scholar 

  17. I. A. M. de Lannoy and K. S. Pang. Diffusional barriers on drug and metabolite kinetics. Drug Metab. Dispos. 15:51–58 (1987).

    CAS  PubMed  Google Scholar 

  18. I. A. M. de Lannoy, F. Barker, III, and K. S. Pang. Formed and preformed metabolite excretion clearances in liver, a metabolite formation organ. Studies with enalapril and enalaprilat in the single pass and recirculating perfused rat liver. J. Pharmacokin. Biopharm. 21:395–422 (1993).

    Article  CAS  Google Scholar 

  19. I. A. M. de Lannoy and K. S. Pang. Combined recirculation of the rat liver and kidney: Studies with enalapril and enalaprilat. J. Pharmacokin. Biopharm. 21:423–456 (1993).

    Article  CAS  Google Scholar 

  20. I. A. M. de Lannoy, R. Nespeca, and K. S. Pang. Renal handling of enalapril and its metabolite, enalaprilat, in the isolated red blood cell-perfused rat kidney. J. Pharmacol. Exp. Ther. 251:1211–1222 (1989).

    CAS  PubMed  Google Scholar 

  21. A. J. Schwab, F. Barker, III, C. A. Goresky, and K. S. Pang. Transfer of enalaprilat across rat liver cell membranes is barrier-limited. Am. J. Physiol. 258(Gastrointest. Liver Physiol. 21):G461–G475 (1990).

    CAS  PubMed  Google Scholar 

  22. K. S. Pang, W. F. Lee, W. F. Cherry, V. Yuen, J. Accaputo, S. Fayz, A. J. Schwab, and C. A. Goresky. Effects of perfusate flow rate on measured blood volume, disse space, intracellular water spaces, and drug extraction in the perfused rat liver preparation: characterization by the technique of multiple indicator dilution technique. J. Pharmacokin. Biopharm. 16:595–632 (1988).

    Article  CAS  Google Scholar 

  23. J. Reichen and G. Paumgartner. Excretory function of the liver. In N. B. Javitt (ed.), Liver and Biliary Tract Physiology I. International Review of Physiology, Vol. 21, University Park Press, Baltimore, MD, 1980, pp. 103–150.

    Google Scholar 

  24. A. J. Schwab, I. A. M. de Lannoy, K. Poon, C. A. Goresky, and K. S. Pang. Enalaprilat handling by the rat kidney: barrier-limited cell entry. Am. J. Physiol. 263(Renal Fluid Electrolyte Physiol. 32):F858–F869 (1992).

    CAS  PubMed  Google Scholar 

  25. W. S. Spector. Handbook of Biological Data, W. B. Saunders, Philadelphia, 1956, pp. 75, 341.

    Google Scholar 

  26. G. R. Wilkinson and D. G. Shand. Commentary. A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther. 18:377–390 (1975).

    CAS  PubMed  Google Scholar 

  27. J. R. Gillette and K. S. Pang. Theoretical aspects of pharmacokinetic drug interactions. Clin. Pharmacol. Ther. 22:623–639 (1977).

    CAS  PubMed  Google Scholar 

  28. K. S. Pang and M. Chiba. Metabolism: Scaling up from in vitro to organ and whole body. In P. G. Welling and L. P. Balant (eds.), Handbook of Experimental Pharmacology, Springer-Verlag, Stuttgart, 1994, pp. 101–187.

    Google Scholar 

  29. F. H. Noormohamed, W. R. McNabb, and A. F. Lant. Pharmacokinetic and pharmacodynamic actions of enalapril in humans: Effect of probenecid pretreatment. J. Pharmacol. Exp. Ther. 253:362–368 (1990).

    CAS  PubMed  Google Scholar 

  30. A. R. Kugler, S. C. Olsen, and D. E. Smith. Tubular transport mechanism of quinapril and quinaprilat in the isolated perfused rat kidney: Effect of organic anions and cations. J. Pharmacokin. Biopharm. 24:349–368 (1996).

    Article  CAS  Google Scholar 

  31. G. L. Sirianni and K. S. Pang. Effect of competing excretion and metabolism on clearance estimates of enalapril in kindey. Pharmacology 97, San Diego [abstract no. 73].

  32. H. Saitoh, C. Gerard, and B. J. Aungst. The secretory intestinal transport of some betalactam antibiotics and anionic compounds: a mechanism contributing to poor oral absorption. J. Pharmacol. Exp. Ther. 278:205–211 (1996).

    CAS  PubMed  Google Scholar 

  33. S. Hsing, Z. Gatmaitan, and I. M. Arias. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa. Gastroenterology 102:897–885 (1992).

    Google Scholar 

  34. M. Inoue, R. Kinne, T. Tran, L. Biempica, and I. M. Arias. Rat liver canalicular membrane vesicles: isolation and topological characterization. J. Biol. Chem. 258:5183–5188 (1983).

    CAS  PubMed  Google Scholar 

  35. A. Szewczuk, H. Milnerowicz, M. V. Polosatov, and K. A. Sobiech. Immunofluorescent localization of gamma-glutamyltransferase in rat and bovine tissues. Acta Histochem. 66:152–159 (1980).

    Article  CAS  PubMed  Google Scholar 

  36. P. Meier, E. Szutl, A Reuben, and J. Boyer. Structural and functional polarity of canalicular and basolateral plasma membrane vesicles isolated in high yield from rat liver. J. Cell Biol. 98:991–1000 (1984).

    Article  CAS  PubMed  Google Scholar 

  37. K. J. Ho, S. C. Hsu, J. S. Chen, and L. H. Ho. Human biliary beta-glucuronidase: correlation of its activity with deconjugation of bilirubin in the bile. Eur. J. Clin. Invest. 16:361–367 (1986).

    Article  CAS  PubMed  Google Scholar 

  38. K. J. Ho, L. H. Ho, and O. R. Kruger. Characterization and determination of the activity of biliary beta-glucuronidase in rats. J. Lab. Clin. Med. 93:916–925 (1979).

    CAS  PubMed  Google Scholar 

  39. A. J. Lança and Y. Israel. Histochemical demonstration of sinusoidal γ-glutamyltransferase activity by substrate protection fixation: Comparative studies in rat and guinea pig liver. Hepatology 14:857–863 (1991).

    Article  PubMed  Google Scholar 

  40. P. Maki. Pathogenesis of calcium bilirubinate gallstone: Role of E. coli, β-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. Ann. Surg. 164:90–100 (1966).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. K. J. Ho, L. H. C. Ho, and O. R. Kruger. Characterization and determination of the activity of biliary β-glucuronidase in rats. J. Lab. Clin. Med. 93:916–925 (1979).

    CAS  PubMed  Google Scholar 

  42. N. Ballatori, R. Jacob, and J. L. Boyer. Intrabiliary glutathione hydrolysis: A source of glutamate in bile. J. Biol. Chem. 261:7860–7865 (1986).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S 2S2, Canada

    Gina L. Sirianni & K. Sandy Pang

  2. Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, M5S 2S2, Canada

    K. Sandy Pang

Authors
  1. Gina L. Sirianni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Sandy Pang
    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

Sirianni, G.L., Pang, K.S. Organ Clearance Concepts: New Perspectives on Old Principles. J Pharmacokinet Pharmacodyn 25, 449–470 (1997). https://doi.org/10.1023/A:1025792925854

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025792925854

Search

Navigation