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Discrepancies in pharmacokinetic parameter estimation between bolus and infusion studies in the perfused rat hindlimb

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Abstract

Isolated, perfused rat hindlimb consists of skeletal muscle, skin, bone, and adipose. Hence, it is a heterogeneous preparation composed of slowly equilibrating tissues of different characteristics and fractional flow rates. This paper shows how caution should be exercised in interpreting the results following bolus administration and subsequent statistical moment analysis of intravascular markers (51Cr-erythrocytes and125I-albumin) and lipophilic barbiturates. For the intravascular markers, the events in the hindlimb are overshadowed by events in the connecting tubing and cannulas, due to their comparable volumes. For the barbiturates, these estimates appear to apply to short-term effects as the volume estimates obtained following infusion to steady state are greater than after bolus administration. For the extravascular markers,14C-sucrose,14C-urea, and3H-water, no such time dependency was shown. However, it is only from the outflow profiles following bolus administration that events in the tissue beds can be elucidated.

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References

  1. N. B. Ruderman, M. N. Goodman, M. Berger, and S. Hagg. Effect of starvation on muscle glucose metabolism: studies with the isolated perfused rat hindquarter.Fed. Proc. 36:171–176 (1977).

    CAS  PubMed  Google Scholar 

  2. W. L. Sexton, R. J. Korthuis, and M. H. Laughlin. Ischaemia-reperfusion injury in isolated rat hindquarters.J. Appl. Physiol. 68:387–392 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. A. Bonen, M. G. Clark, and E. J. Henriksen. Experimental approaches in muscle metabolism: hindlimb perfusion and isolated muscle incubations.Am. J. Physiol. 266:E1-E16 (1994).

    CAS  PubMed  Google Scholar 

  4. J. M. Díaz-García, A. M. Evans, and M. Rowland. Application of the axial dispersion model of hepatic drug elimination to the kinetics of diazepam in the isolated perfused rat liver.J. Pharmacokin. Biopharm. 20:171–193 (1992).

    Article  Google Scholar 

  5. R. Hori, Y. L. He, Y. Saito, A. Kamiya, and Y. Tanigawara. Moment analysis of drug distribution in kidney. V:In vivo transepithelial transport of p-aminohippurate in rat kidney.J. Pharmacokin. Biopharm. 19:51–70 (1991).

    Article  CAS  Google Scholar 

  6. T. Sakane, M. Nakatsu, A. Yamamoto, M. Hashida, H. Sezaki, S. Yamashita, and T. Nadai. Assessment of drug disposition in the perfused rat brain by statistical moment analysis.Pharm. Res. 8:683–689 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. P. L. Williams and J. E. Riviere. Estimation of physiological volumes in the isolated perfused porcine skin flap.Res. Commun. Chem. Pathol. Pharmacol. 66:145–158 (1989).

    CAS  PubMed  Google Scholar 

  8. R. Gubser, C. DiFrancesco, and M. H. Bickel. Uptake of lipophilic model compounds into the isolated perfused rat epididymal adipose tissue.J. Pharmacol. Exp. Ther. 237:967–971 (1986).

    CAS  PubMed  Google Scholar 

  9. T. Kakutani, K. Yamaoka, M. Hashida, and H. Sezaki. A new method for assessment of drug disposition in muscle: application of statistical moment theory to local perfusion systems.J. Pharmacokin. Biopharm. 13:609–631 (1985).

    Article  CAS  Google Scholar 

  10. Z. Y. Wu, L. P. Rivory, and M. S. Roberts. Physiological pharmacokinetics of solutes in the isolated perfused rat hindlimb: characterization of the physiology with changing perfusate flow, protein content and temperature using statistical moment analysis.J. Pharmacokin. Biopharm. 21:653–688 (1993).

    Article  CAS  Google Scholar 

  11. A. C. Heatherington and M. Rowland. Estimation of reference spaces in the perfused rat hindlimb.Eur. J. Pharm. Sci. 2:261–270 (1994).

    Article  CAS  Google Scholar 

  12. S. Toon and M. Rowland. Structure-pharmacokinetic relationships among the barbiturates in the rat.J. Pharmacol. Exp. Ther. 225:752–763 (1983).

    CAS  PubMed  Google Scholar 

  13. A. C. Heatherington and M. Rowland. Development of a physiologically-based pharmacokinetic model in the rat hindlimb preparation: estimation of reference spaces.J. Pharm. Pharmacol. 45(Suppl. 2):1116 (1993).

    Google Scholar 

  14. A. C. Heatherington and M. Rowland Distribution of 5-alkyl-5-ethyl barbituric acids in the perfused rat hindlimb.Eur. J. Pharm. Sci. 2(1, 2):113 (1994).

    Article  Google Scholar 

  15. L. Balk, J. Meijer, J. W. DePierre, and L. E. Appelgreen. The uptake and distribution of3H-benzo[a]pyrene in the Northern pike (Esox lucius). Examination by whole-body autoradiography and scintillation counting.Toxicol. Appl. Pharmacol. 74:430–449 (1984).

    Article  CAS  PubMed  Google Scholar 

  16. N. Benowitz, R. P. Forsyth, K. L. Melmon, and M. Rowland. Lidocaine disposition kinetics in monkey and man. I. Prediction by a perfusion model.Clin. Pharmacol. Ther. 16:87–98 (1974).

    CAS  PubMed  Google Scholar 

  17. H. S. Chen and J. F. Gross. Estimation of tissue-to-plasma partition coefficients used in physiological pharmacokinetic models.J. Pharmacokin. Biopharm. 7:117–125 (1979).

    Article  CAS  Google Scholar 

  18. S. Björkman, D. R. Stanski, D. Verotta, and H. Harashima. Comparative tissue concentration profiles of fentanyl and alfentanil in humans predicted from tissue/blood partition data obtained in rats.Anesthesiology 72:865–873 (1990).

    Article  PubMed  Google Scholar 

  19. S. W. Martin, A. J. Stevens, B. S. Brennan, M. L. Reis, M. Rowland, and J. B. Houston. Regional drug delivery: Permeability characteristics of the rat 6-day-old air pouch model of inflammation.Pharm. Res. (in press).

  20. E. Nara, M. Masegi, T. Hatono, and M. Hashida. Pharmacokinetic analysis of drug absorption from muscle based on a physiological diffusion model: effect of molecular size on absorption.Pharm. Res. 9:161–168 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. K. S. Pang, F. Barker, A. J. Schwab, and G. A. Goresky.14C urea and58Co EDTA as reference indicators in hepatic multiple indicator dilution studies.Am. J. Physiol. 259:G32-G40 (1990).

    CAS  PubMed  Google Scholar 

  22. R. L. Dedrick, M. F. Flessner, J. M. Collins, and J. S. Schultz. A distributed model of peritoneal transport. InFrontiers in Peritoneal Dialysis, Field, Rich, and Associates, New York, 1986, pp. 31–36.

    Chapter  Google Scholar 

  23. R. Studer and J. Potchen. The radioisotopic assessment of regional microvascular permeability to macromolecules.Microvasc. Res. 3:35–48 (1971).

    Article  CAS  PubMed  Google Scholar 

  24. L. Bent-Hansen. Whole body capillary exchange of albumin.Acta Physiol. Scand. 603(Suppl.):5–10 (1991).

    CAS  Google Scholar 

  25. H. Wiig, M. DeCarlo, L. Sibley, and E. M. Renkin. Interstitial exclusion of albumin in rat tissues measured by a continuous infusion method.Am. J. Physiol. 263:H1222-H1233 (1992).

    CAS  PubMed  Google Scholar 

  26. B. Haraldsson. Physiological studies of macromolecular transport across capillary walls. Studies on continuous capillaries in rat skeletal muscle.Acta Physiol. Scand. 553(Suppl.):1–40 (1986).

    CAS  Google Scholar 

  27. C. A. Goresky. A linear method for determining liver sinusoidal and extravascular volumes.Am. J. Physiol. 204:626–640 (1963).

    CAS  PubMed  Google Scholar 

  28. R. Kawai, A. Nakashima, I. Akasaka, Y. Takahashi, and M. Ohtawa. Measurement of vascular, interstitial and intracellular volumes in rats. Advances in Simultaneous Pharmacokinetic/Pharmacodynamic Modelling, 2nd International Symposium, The Netherlands, 1994.

  29. A. C. Heatherington. A physiological based pharmacokinetic model for drug distribution. Ph.D. Thesis. University of Manchester, England (1994).

    Google Scholar 

  30. C. A. Goresky and M. Silverman. Effect of correction of catheter distortion on calculated liver sinusoidal volumes.Am. J. Physiol. 207:883–892 (1964).

    CAS  PubMed  Google Scholar 

  31. L. Bent-Hansen. Initial plasma disappearance and tissue uptake of131I-albumin in normal rabbits.Microvasc. Res. 41:345–356 (1991).

    Article  CAS  PubMed  Google Scholar 

  32. L. Bent-Hansen. Initial plasma disappearance and distribution volume of131I-albumin and125I-fibrinogen in man.Acta Physiol. Scand. 136:455–461 (1989).

    Article  CAS  PubMed  Google Scholar 

  33. P. Sejrsen, W. P. Paaske, and O. Henriksen. Capillary permeability of131I-albumin in skeletal muscle.Microvasc. Res. 29:265–281 (1985).

    Article  CAS  PubMed  Google Scholar 

  34. M. Ichikawa, S. C. Tsao, T. H. Lin, S. Miyauchi, Y. Sawada, T. Iga, M. Hanano, and Y. Sugiyama. Albumin-mediated transport phenomenon observed for ligands with high membrane permeability. Effect of the unstirred water layer in the Disse space of rat liver.J. Hepatol. 16:38–49 (1992).

    Article  CAS  PubMed  Google Scholar 

  35. B. B. Brodie, J. J. Burns, L. C. Mark, P. A. Lief, E. Bernstein, and E. M. Papper. The fate of pentobarbital in man and dog and a method for its estimation in biological material.J. Pharmacol. Exp. Ther. 109:26–34 (1953).

    CAS  PubMed  Google Scholar 

  36. Y. Igari, Y. Sugiyama, S. Awazu, and M. Hanano. Comparative physiologically based pharmacokinetics of hexobarbital, phenobarbital, and thiopental in the rat.J. Pharmacokin. Biopharm. 10:53–75 (1982).

    Article  CAS  Google Scholar 

  37. R. N. Upton, C. Nancarrow, C. F. McLean, L. E. Mather, and W. B. Runciman. Thein vivo blood, fat and muscle concentrations of lignocaine and bupivacaine in the hindquarters of sheep.Xenobiotica 21:13–22 (1991).

    Article  CAS  PubMed  Google Scholar 

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  1. Anne C. Heatherington

    Present address: Center for Bioengineering, University of Washington, Box 352255, 98195, Seattle, Washington

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  1. Pharmacy Department, University of Manchester, Oxford Road, M13 9PL, Manchester, UK

    Anne C. Heatherington & Malcolm Rowland

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Heatherington, A.C., Rowland, M. Discrepancies in pharmacokinetic parameter estimation between bolus and infusion studies in the perfused rat hindlimb. Journal of Pharmacokinetics and Biopharmaceutics 23, 441–462 (1995). https://doi.org/10.1007/BF02353468

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