Skip to main content
Log in

Interspecies Scaling of Bosentan, A New Endothelin Receptor Antagonist and Integration of in Vitro Data into Allometric Scaling

Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. The goal of this study was to find a rational and reliable method of using animal data to predict the clearance of metabolised drugs in humans.

Methods. One such approach is to use in vitro liver models (e.g. hepatocytes and microsomes) to determine the relative capacities of the various animal species and humans to metabolise the test compound. These data can then be combined with the in vivo clearances in animals, to calculate the in vivo clearance in humans using allometric scaling techniques. In this study, this approach was evaluated with a new endothelin receptor antagonist, bosentan, which is eliminated mainly through metabolism and is characterized by very large interspecies differences in clearance. Therefore, this compound provided a stringent test of our new extrapolation method for allometric scaling.

Results. The results obtained with bosentan showed that adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro gave a far better prediction of human clearance than an empirical correcting factor (brain weight).

Conclusions. This approach provided a more rational basis for predicting the clearance of metabolised compounds in humans.

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

Access this article

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. Y. Sawada, M. Hanano, Y. Sugiyama, and T. Iga. Prediction of the disposition of beta-lactam antibiotics in humans from pharmacokinetic parameters in animals. J. Pharmacokinet. Biopharm. 12:241–61 (1984).

    Google Scholar 

  2. B. Boxenbaum, and R. W. D'Souza. Interspecies Pharmacokinetic Scaling, Biological Design and Neoteny. In B. Testa (eds.), Advances in Drug Research, Academic Press Limited, London, 1990, pp. 139–196.

    Google Scholar 

  3. P. J. McNamara. Interspecies scaling in pharmacokinetics. In P. G. Welling, F. L. S. Tse and S. V. Dighe (eds.), Pharmaceutical bioequivalence, Marcel Dekker, New York, 1991, pp. 267–300.

    Google Scholar 

  4. D. B. Campbell. Can allometric interspecies scaling be used to predict human kinetics. Drug Inf. J. 28:235–245 (1994).

    Google Scholar 

  5. H. Boxenbaum, and J. B. Fertig. Scaling of antipyrine intrinsic clearance of unbound drug in 15 mammalian species. Eur. J. Drug Metab. Pharmacokinet. 9:177–83 (1984).

    Google Scholar 

  6. T. Lave, A. H. Schmitt-Hoffmann, P. Coassolo, G. Ubeaud, B. Vallès, B. Ba, R. Brandt, and R. C. Chou. A new extrapolation method from animal to man; application to a metabolized compound, mofarotene. Life Sci. 56:473–478 (1995).

    Google Scholar 

  7. C. Von Bahr, C.-G. Groth, H. Jansson, G. Lundgren, M. Lind, and H. Glaumann. Drug metabolism in human liver in vitro: Establishment of a human liver bank. Clin. Pharm. Ther. 27:711–725 (1980).

    Google Scholar 

  8. P. O. Seglen. Preparation of isolated rat liver cells. Meth. Cell Biol. 13:29–83 (1976).

    Google Scholar 

  9. T. Seddon, I. Michelle, and R. J. Chenery. Comparative drug metabolism of diazepam in hepatocytes isolated from man, rat, monkey and dog. Biochem. Pharmacol. 38:1657–1665 (1989).

    Google Scholar 

  10. J. Mordenti. Man versus beast: pharmacokinetic scaling in mammals. J. Pharm. Sci. 75:1028–40 (1986).

    Google Scholar 

  11. J. B. Houston. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem. Pharmacol. 47:1469–1479 (1994).

    Google Scholar 

  12. K. S. Pang, P. Kong, J. A. Terrell, and R. E. Billings. Metabolism of acetaminophen and phenacetin by isolated rat hepatocytes. A system in which the spatial organization inherent in the liver is disrupted. Drug Metab. Dispos. 13:42–50 (1985).

    Google Scholar 

  13. A. Rane, G. R. Wilkinson, and D. G. Shand. Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance. J. Pharmacol. Exp. Ther. 200:420–4 (1977).

    Google Scholar 

  14. B. A. Hoener. Predicting the hepatic clearance of xenobiotics in humans from in vitro data. Biopharm. Drug Dispos. 15:295–304 (1994).

    Google Scholar 

  15. C. Bäärnhielm, H. Dählback, and I. Skanberg. In vivo pharmacokinetics of felodipine predicted from in vitro studies in rat, dog and man. Acta Pharm. Toxicol. 59:113–22 (1986).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lave, T., Coassolo, P., Ubeaud, G. et al. Interspecies Scaling of Bosentan, A New Endothelin Receptor Antagonist and Integration of in Vitro Data into Allometric Scaling. Pharm Res 13, 97–101 (1996). https://doi.org/10.1023/A:1016037519116

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016037519116

Navigation