Skip to main content
SpringerLink
Log in

Combined recirculation of the rat liver and kidney: Studies with enalapril and enalaprilat

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

Abstract

Combined recirculation of the rat liver (L) and kidney (IPK) at 10 ml min−1 per organ (LK) was developed to examine the hepatorenal handling of the precursor-metabolite pair: [14C]-enalapril and [3H]enalaprilat. Loading doses followed by constant infusion of [14C]enalapril and preformed [3H]enalaprilat to the reservoirs of the IPK or the LK preparation was used to achieve steady stale conditions. In both organs, enalapril was mostly metabolized to its dicarboxylic acid metabolite, enalaprilat, which was excreted unchanged. At steady state, the fractional excretion for [14C]enalapril (FE=0.45 to 0.48) and preformed [3H]enalaprilat (FE{pmi}=1.1) were constant and similar for both the IPK and LK. The additivity of clearance was demonstrated in the LK preparation, namely, the total clearance of enalapril was the sum of its hepatic and renal clearances. However, the apparent fractional excretion for fanned [14C]enalaprilat, FE{mi} and the apparent urinary clearance were time-dependent and higher than the corresponding values for preformed [3H]enalaprilat in both the IPK and LK. The FE{mi} and urinary clearance values further differed between the IPK and LK. Biliary clearance of formed vs. preformed enalaprilat displayed the same discrepant trends as observed for FE{mi} vs. FE{pmi} for the LK. These observations on the time-dependent and variable excretory clearance (urinary or biliary) of the formed metabolite vs. the constant, and much reduced, excretory clearance of the preformed metabolite are due to dual contributions to formed metabolite excretion: the nascently formed, intracellular metabolite which immediately underwent excretion and the formed metabolite which reentered the circulation, behaved as a preformed species. When data for the IPK and LK preparations were modeled with a physiological model with parameters previously reported for the L and IPK, all data, including metabolite excretory clearances, were well predicted. Model simulations revealed that the apparent FE{mi} differed between the LK and IPK preparations when the liver was present as an additional metabolite formation organ; the apparent excretory (urinary or

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

Abbreviations

k0 :

infusion rate into the reservoir

CR :

reservoir concentration

COut,k and COut,L :

venous concentrations for the kidney and liver

Cp,k and cP,L :

concentrations in renal and hepatic plasma, respectively

Ck and CL :

concentrations in kidney and liver tissue, respectively

CU and CBile :

concentrations in urine and bile, respectively

CL inb andCL ef b :

influx and efflux clearances, respectively, at the basolateral membrane of the renal tubular cell

C inl and CL efl :

influx and efflux clearances, respectively, at the luminal membrane of the renal tubular cell

CL mint,K :

renal metabolic intrinsic clearance of the drug

CL ind and CL efd :

influx and efflux clearances, respectively, at the sinusoidal membrane

CL m,Lint :

hepatic metabolic intrinsic clearance of the drug

CL bint,L :

biliary intrinsic clearance

VR :

plasma reservoir volume

VP,K and VP,L :

plasma volumes of the kidney and liver, respectively

VK and VL :

tissue volumes of the kidney and liver, respectively

VU and VBile :

volumes of urine and bile, respectively

QK and QL :

total renal and hepatic plasma flow rates, respectively

GFR :

glomerular filtration rate

QU and QBile :

urine and bile flow rates, respectively

fP, fK, and fL :

unbound fractions in plasma and kidney and liver tissue, respectively

References

  1. H. Daugaard, M. Egfjord, and K. Olgaard. Isolated perfused rat kidney and liver combined.Pflügers Arch. 409:220–222 (1987).

    Article  CAS  PubMed  Google Scholar 

  2. M. Yasuhara, H. Kataymaa, J. Fujiwara, K. Okumura, and R. Hori. Influence of acute renal failure on pharmacokinetics of phenosulfophthalein in rats: A comparative studyin vivo and in the simultaneous perfusion system of liver and kidney.J. Pharmacobiodyn. 8:377–384 (1985).

    Article  CAS  PubMed  Google Scholar 

  3. D. Alcorn, K. R. Emslie, B. D. Ross, G. B. Ryan, and J. D. Tange. Selective distal nephron damage during isolated kidney perfusion.Kidney Int. 19:638–647 (1981).

    Article  CAS  PubMed  Google Scholar 

  4. M. Brezis, S. Rosen, P. Silva, and F. H. Epstein. Selective vulnerability of the medullary thick ascending limb to anoxia in the isolated perfused rat kidney.J. Clin. Invest. 73:182–190 (1984).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. K. S. Pang, W. F. Cherry, J. A. Terrell, and E. H. Ulm. Disposition of enalapril and its diacid metabolite, enalaprilat, in a perfused rat liver preparation. Presence of a diffusional barrier into hepatocytes.Drug Metab. Dispos. 12:309–313 (1984).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  7. 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  Google Scholar 

  8. I. A. M. de Lannoy and K. S. Pang. Commentary: Presence of a diffusional barrier on metabolite kinetics: enalaprilat as a generatedversus preformed metabolite.Drug Metab. Dispos. 14:513–520 (1986).

    PubMed  Google Scholar 

  9. 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:G461-G475 (1990).

    CAS  PubMed  Google Scholar 

  10. 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:F858-F869 (1992).

    CAS  PubMed  Google Scholar 

  11. B. D. Ross.Perfusion Techniques in Biochemistry. A Laboratory Manual, Clarendon, Oxford, 1972, pp. 135–257.

    Google Scholar 

  12. F. H. Epstein, J. T. Brosnan, J. D. Tange, and B. D. Ross. Improved function with amino acids in the isolated perfused kidney.Am. J. Physiol. 243:F284-F292 (1982).

    CAS  PubMed  Google Scholar 

  13. R. J. Henry, N. Chiamori, O. J. Golub, and S. Berkman. Revised spectrophotometric methods for the determination of glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase and lactic acid dehydrogenase.Am. J. clin. Pathol. 34:381–398 (1960).

    CAS  PubMed  Google Scholar 

  14. A. Heyrovsky. A new method for the determination of insulin in plasma and urine.Clin. Chim. Acta 1:470–474 (1956).

    Article  CAS  PubMed  Google Scholar 

  15. O. H. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with the folin phenol reagent.J. Biol. Chem. 193:265–275 (1951).

    CAS  PubMed  Google Scholar 

  16. D. J. Tocco, F. A. de Luna, A. E. W. Duncan, T. C. Vassil, and E. H. Ulm. The physiological disposition and metabolism of enalapril maleate in laboratory animals.Drug Metab. Dispos. 10:15–19 (1982).

    CAS  PubMed  Google Scholar 

  17. J. W. Severinghaus. Blood gas calculator.J. Appl. Physiol. 21:1108–1116 (1966).

    CAS  PubMed  Google Scholar 

  18. R. M. Winslow, M.-L. Swenberg, R. L. Berger, R. I. Shrager, M. Luzzana, M. Samaja, and L. Rossi-Bernardi. Oxygen equilibrium curve of normal blood and its evaluation by Adair's equation.J. Biol. Chem. 225:2331–2337 (1977).

    Google Scholar 

  19. 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  Google Scholar 

  20. K. S. Pang, W. F. Cherry, and E. H. Ulm. Disposition of enalapril in the intestine-liver preparation: Absorption, metabolism, and first-pass effects.J. Pharmacol. Exp. Ther. 233:788–795 (1985).

    CAS  PubMed  Google Scholar 

  21. E. Bojesen. The function of the urinary tract as a “dead space” in renal clearance experiments. Scand.J. Lab. Invest. 1:290–294 (1949).

    Article  Google Scholar 

  22. 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 

  23. K. S. Pang, W. F. Cherry, V. Yuen, J. Accaputo, S. Fayz, W.-F. Lee, 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 

  24. M. V. St-Pierre, W.-F. Lee, A. J. Schwab, C. A. Goresky, and K. S. Pang. The multiple indicator dilution technique for characterization of normal and retrograde flow in oncethrough rat liver perfusions.Hepatology 9:285–296 (1989).

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  26. 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, MD, 1980, pp. 103–150.

    Google Scholar 

  27. E. D. Frohlich. Vascular effects of the Krebs intermediate metabolites.Am. J. Physiol. 208:149–153 (1965).

    CAS  PubMed  Google Scholar 

  28. B. M. Brenner, T. W. Meyer, and T. H. Hostetter. Dietary protein intake and the progressive nature of kidney disease: The role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease.New Engl. J. Med. 307:652–659 (1982).

    Article  CAS  PubMed  Google Scholar 

  29. M. Brezis, S. Rosen, J. S. Stoff, K. Spokes, P. Silva, P. Epstein. and F. H. Epstein. Inhibition of prostaglandin synthesis in rat kidney perfused with and without erythrocytes: Implication for analgesic nephropathy.Min. Electro. Metab. 12:326–332 (1986).

    CAS  Google Scholar 

Download references

Author information

Author notes

  1. Ines A. M. de Lannoy

    Present address: Membrane Biology Group, University of Toronto, M5S 1A1, Toronto, Canada

Authors and Affiliations

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

    Ines A. M. de Lannoy & K. Sandy Pang

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

    K. Sandy Pang

Authors
  1. Ines A. M. de Lannoy
    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

Additional information

This work was supported by the Medical Research Council of Canada. I. A. M. de Lannoy was a recipient of the Ontario Graduate Scholarship from the Ontario Ministry of Health; K. S. Pang was a recipient of the Faculty Development Award, Medical Research Council.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Lannoy, I.A.M., Pang, K.S. Combined recirculation of the rat liver and kidney: Studies with enalapril and enalaprilat. Journal of Pharmacokinetics and Biopharmaceutics 21, 423–456 (1993). https://doi.org/10.1007/BF01061690

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01061690

Key words

Search

Navigation