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Physiologically based pharmacokinetic model for the renal clearance of phenolsulfonphthalein and the interaction with probenecid and salicyluric acid in the dog

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Abstract

Plasma kinetics and renal excretion of intravenous phenolsulfonphthalein (PSP, 1.0 g), with and without concomitant administration of probenecid or salicyluric acid (SUA), were studied in the Beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by probenecid and SUA. A physiologically based kidney model was developed that incorporates the functional characteristics of the kidney that determine the excretion of PSP, i.e., renal plasma flow, urine flow, nonlinear protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. The interaction with probenecid and SUA could be adequately described with the model by inhibition of the carrier-mediated uptake of PSP into the proximal tubular cells. However, both compounds clearly differed in their inhibitory action. Whereas probenecid showed simple competitive inhibition, for SUA a considerably more complex interaction (two- site competitive system) had to be taken into consideration. Especially in the interaction experiments, only satisfactory fits to the model were obtained when secretion was assumed to be dependent on unbound PSP concentrations. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of PSP within the proximal tubular cells, which was clearly diminished in presence of probenecid or SUA. The predicted accumulation ratios were in good agreement with previous studies.

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References

  1. E. K. Marshall and J. L. Vickers. The mechanism of the elimination of phenolsulfon- phthalein by the kidney; a proof of secretion by the convoluted tubules.Bull. Johns Hopkins Hosp. 34:1–7 (1923).

    Google Scholar 

  2. B. K. Ochwadt and R. F. Pitts. Disparity between phenol red and diodrast clearances in the dog.Am. J, Physiol 187:318–322 (1956).

    CAS  Google Scholar 

  3. A. Heidland and E. Riedl. Renaler Phenolsulfonphthalein-Transport nach Sulfonamid- bedingter Entkoppelung der Farbstoff-Plasmabindung.Klin. Wochenschr. 15:816–820 (1968).

    Article  Google Scholar 

  4. R. Hori, K. Sunayashiki, and A. Kamiya. Tissue distribution and metabolism of drugs. I. Quantitative investigation on renal handling of phenolsulfonphthalein and sulfonamides in rabbits.Chem. Pharm. Bull. 26:740–745 (1978).

    Article  CAS  PubMed  Google Scholar 

  5. U. Gerdes, J. Kristensen, J. V. MØller, and M. I. Sheikh. Renal handling of phenol red. III. Bidirectional transport.J. Physiol 227:115–129 (1975).

    Google Scholar 

  6. H. W. Smith.The kidney: Structure and function in health and disease, Oxford University Press, New York, 1951.

    Google Scholar 

  7. H. W. Smith, W. Goldring, and H. Chasis. The measurement of the tubular excretory mass, effective blood flow and filtration rate in the normal human kidney.J. Clin. Invest. 17:263–278 (1938).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. M. I. Sheikh. Renal handling of phenol red. I. A comparative study on the accumulation of phenol red andp-aminohippurate in rabbit kidney tubules in vitro.J. Physiol. 227:565–590 (1972).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. G. A. Tanner, P. K. Carmines, and W. B. Kinter. Excretion of phenol red by the Necturus kidney.Am. J. Physiol. 236:F442–447 (1979).

    CAS  PubMed  Google Scholar 

  10. I. M. Weiner, J. A. Washington, and G. H. Mudge. On the mechanism of action of probenecid on renal tubular secretion.Bull. Johns Hopkins Hasp. 106:333–346 (1972).

    Google Scholar 

  11. W. Braun. Zum Mechanismus der gegenseitigen Hemmung von Phenolrot, Paraaminohippursaure und Probenecid.Arch. Exp. Pathol. Pharmak. 239:400–409 (1960).

    Article  CAS  Google Scholar 

  12. P. Hekman and C. A. M. van Ginneken. Simultaneous kinetic modelling of plasma levels and urinary excretion of salicyluric acid and the influence of probenecid.Eur. J. Drug Metab, Pharmacokin. 3:239–249 (1983).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  14. F. G. M. Russel, A. C. Wouterse, P. Hekman, G. J. Grutters, and C. A. M. van Ginneken. Quantitative urine collection in renal clearance studies in the dog.J. Pharmacol. Method 17:125–136 (1987).

    Article  CAS  Google Scholar 

  15. A. Heyrovski. A new method for the determination of inulin in plasma and urine.Clin. Chim. Acta 1:470–474 (1956),

    Article  Google Scholar 

  16. P. Hekman, P. A. T. W. Porskamp, H. C. J. Ketelaars, and C. A. M. van Ginneken. Rapid high-performance liquid chromatographic method for the determination of probenecid in biological fluids.J. Chrom. 182:252–256 (1980).

    Article  CAS  Google Scholar 

  17. C. M. Metzler, G. L. Elfring, and A. J. McEwen. A package of computer programs for pharmacokinetic modelling.Biometrics 30:562–563 (1974).

    Article  Google Scholar 

  18. W. L. Chiou. Critical evaluation of potential error in pharmacokinetic studies using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve.J. Pharmacokin. Biopharm. 6:539–546 (1978).

    Article  CAS  Google Scholar 

  19. K. Yamaoka, T. Nakagawa, and T. Uno. Statistical moments in pharmacokinetics.J. Pharmacokin. Biopharm. 6:547–558 (1978).

    Article  CAS  Google Scholar 

  20. L. Z. Benet and R. L. Galeazzi. Noncompartmental determination of the steady-state volume of distribution.J. Pharm. Sci. 68:1071–1074 (1979).

    Article  CAS  PubMed  Google Scholar 

  21. M. Gibaldi and D. Perrier.Pharmacokinetics, Marcell Dekker, New York, 1982.

    Google Scholar 

  22. B. H. Ewald. Renal function tests in normal Beagle dogs.Am. J. Vet. Res. 28:741–749 (1967).

    CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  24. F. P. Chinard. Comparative renal excretion of glomerular substances following instantaneous injection into a renal artery.Am. J. Physiol. 180:617–619 (1955).

    CAS  PubMed  Google Scholar 

  25. M. S. Dunnill and W. Halley. Some observations on the quantitative anatomy of the kidney.J. Pathol. 110:113–121 (1973).

    Article  CAS  PubMed  Google Scholar 

  26. I. H. Segel.Enzyme kinetics, Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems, Wiley, New York, 1975.

    Google Scholar 

  27. J. V. MØller and M. I. Sheikh. Renal organic anion transport system: pharmacological, physiological, and biochemical aspects.Pharmacol. Rev. 34:315–358 (1983).

    Google Scholar 

  28. I. M. Weiner. Transport of weak acids and bases. In J. Orloff and R. W. Berliner (eds.),Handbook of Physiology, American Physiological Society, Washington DC, 1973, pp. 521–554.

    Google Scholar 

  29. R. P. Forster and J. H. Copenhaver. Intracellular accumulation as an active process in a mammalian renal transport system in vitro.Am. J. Physiol. 186:167–171 (1956).

    CAS  PubMed  Google Scholar 

  30. M. I. Sheikh and J. V. MØller. Renal handling of phenol red. IV. Tubular localization in rabbit and rat kidney in vivo.Am. J. Physiol. 238:F159–165 (1980).

    CAS  PubMed  Google Scholar 

  31. R. H. Bowman. Renal secretion of [35S]-furosemide and its depression by albumin binding.Am. J. Physiol. 229:93–98 (1975).

    CAS  PubMed  Google Scholar 

  32. S. Hall and M. Rowland. Influence of fraction unbound upon the renal clearance of furosemide in the isolated perfused rat kidney.J. Pharmacol. Exp. Ther. 232:263–268 (1985).

    CAS  PubMed  Google Scholar 

  33. A. Kamiya, K. Okumura, and R. Hori. Quantitative investigation on renal handling of drugs in rabbits, dogs, and humans.J. Pharm. Sci. 72:440–443 (1983).

    Article  CAS  PubMed  Google Scholar 

  34. J. H. Gustafson and L. Z. Benet. Saturable kinetics of intravenous chlorothiazide in the rhesus monkey.J. Pharmacokin. Biopharm. 9:461–476 (1981).

    Article  CAS  Google Scholar 

  35. I. Bekersky, A. C. Popick, and W. A. Colburn. Influence of protein binding and metabolic interconversion on the disposition of sulfisoxazole and its N4-acetyl metabolite by the isolated perfused rat kidney.Drug Metab. Disp. 12:607–613 (1984).

    CAS  Google Scholar 

  36. E. Marshall. The secretion of phenol red by the mammalian kidney.Am. J. Physiol. 99:77–86 (1931).

    CAS  Google Scholar 

  37. H. L. Sheehan. The renal elimination of phenol red in the dog.J. Physiol. 87:237–253 (1936).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. C. K. Ross and P. D. Holohan. Transport of organic anions and cations in isolated renal plasma membranes.Ann. Rev. Pharmacol. Toxicol. 23:65–85 (1983).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, University of Nijmegen, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands

    Frans G. M. Russel, Alfons C. Wouterse & Cees A. M. van Ginneken

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  1. Frans G. M. Russel
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  2. Alfons C. Wouterse
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  3. Cees A. M. van Ginneken
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These investigations were supported by the Foundation for Medical Research MEDIGON.

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Russel, F.G.M., Wouterse, A.C. & van Ginneken, C.A.M. Physiologically based pharmacokinetic model for the renal clearance of phenolsulfonphthalein and the interaction with probenecid and salicyluric acid in the dog. Journal of Pharmacokinetics and Biopharmaceutics 15, 349–368 (1987). https://doi.org/10.1007/BF01066518

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