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Isotope effects on pathways of metabolism

  • M. G. Horning
  • K. Lertratanangkoon
  • K. D. Haegele
  • K. Brendel

Abstract

In recent studies (Horning et al., 1976) we have shown that the metabolism of a drug may be shifted by deuterium labelling if the drug is metabolised by multiple alternative pathways. Deuterated analogues of caffeine (1-trideuteromethyl3,7-dimethylxanthine and 7-trideuteromethyl-1,3-dimethylxanthine) and antipyrine (2-trideuteromethyl-3-methyl- and 2-methyl-3-trideuteromethyl1-phenyl-3-pyrazoline-5-one) were employed. The oxidation of the —CD3 group was depressed and the metabolism was shifted to other pathways that did not involve cleavage of a carbon—deuterium bond. The change in metabolic pathways, like the primary isotope effect, occurs when deuterium is substituted at a principal site of metabolism and when oxidation is a primary mode of metabolism. However, this response, which we have observed in both in vivo and in vitro experiments, is different from the primary isotope effect, which is usually defined as the ratio of rate constants (kH/kD) or ratio of products formed [H]/[D]. For this reason we have used the term ‘metabolic switching’ to describe the effect of deuterium substitution on compounds that are metabolised by multiple alternative pathways rather than sequentially.

Keywords

Isotope Effect Trimethylsilyl Ether Metabolic Switching Deuterium Labelling Aromatic Hydroxylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Blake, M. I., Crespi, H. L. and Katz, J. J. (1975). J. Pharm. Sci., 64, 367CrossRefGoogle Scholar
  2. Chang, T. and Glazko, A. J. (1972). Antiepileptic Drugs (ed. D. M. Woodbury, J. K. Penry and R. P. Schmidt), Raven Press, New York, p. 149Google Scholar
  3. Chen, G., Portman, R. and Ensor, C. R. (1951). J. Pharmacol. Exp. Ther., 103, 54Google Scholar
  4. Cox, P. J., Farmer, P. B., Foster, A. B., Gilby, E. D. and Jarman, M. (1976). Cancer Treatment Rep., 60, 483Google Scholar
  5. Dudley, K. H., Bius, D. L. and Grace, M. E. (1972). J. Pharmacol. Exp. Ther., 180, 167Google Scholar
  6. Harvey, D. J., Glazener, L., Stratton, C., Nowlin, J., Hill, R. M. and Horning, M. G. (1972). Res. Commun. Chem. Pathol. Pharmacol., 3, 557Google Scholar
  7. Harvey, D. J., Nowlin, J., Hickert, P., Butler, C., Gansow, O. and Horning, M. G. (1974). Biomed. Mass. Spectrom., 1, 340CrossRefGoogle Scholar
  8. Horning, M. G., Butler, C., Harvey, D. J., Hill, R. M. and Zion, T. E. (1973). Res. Commun. Chem. Pathol. Pharmacol., 6, 565Google Scholar
  9. Horning, M. G., Gregory, P., Nowlin, J., Stafford, M., Lertratanangkoon, K., Butler, C., Stillwell, W. G. and Hill, R. M. (1974). Clin. Chem., 20, 282Google Scholar
  10. Horning, M. G., Haegele, K. D., Sommer, K. R., Nowlin, J., Stafford, M. and Thenot, J.-P. (1976). Proceedings of the Second International Conference on Stable Isotopes in Chemistry, Biology and Medicine (ed. R. Klein and P. Klein), US Atomic Energy Commission, Oak Ridge, Tennessee, p. 41Google Scholar
  11. Maynert, E. W. (1972). Antiepileptic Drugs (ed. D. M. Woodbury, J. K. Penry and R. P. Schmidt), Raven Press, New York, p. 311Google Scholar
  12. Nicholls, P. J. and Orton, T. C. (1972). Brit. J. Pharmacol., 45, 48CrossRefGoogle Scholar
  13. Strong, J. M., Abe, T., Gibbs, E. L. and Atkinson, A. J., Jr. (1974). Neurology, 24, 250CrossRefGoogle Scholar
  14. Tomaszewski, J. E., Jerina, D. M. and Daly, J. W. (1975). Biochemistry, 14, 2024CrossRefGoogle Scholar
  15. Zimmerman, E. T. (1953). Am. J. Psychiatry, 109, 767CrossRefGoogle Scholar

Copyright information

© The Contributors 1978

Authors and Affiliations

  • M. G. Horning
    • 1
  • K. Lertratanangkoon
    • 1
  • K. D. Haegele
    • 2
  • K. Brendel
    • 3
  1. 1.Baylor College of MedicineHoustonUSA
  2. 2.University of Texas Health Science CenterSan AntonioUSA
  3. 3.University of ArizonaTucsonUSA

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