Rapid multi-component detection of fluorinated drug metabolites in whole urine from a ‘cassette’ dose study using high resolution ¹⁹F NMR spectroscopy

Abstract

High resolution ¹⁹F NMR spectroscopy has been successfully applied to the analysis of drug metabolites in whole rat urine from a ‘cassette’ dose study of 6 fluorinated test compounds dosed at 10 mg kg^–1 per compound. A total of 21 compound-related molecules were rapidly detected in the 0–8 h urine samples. The metabolic fate of the compounds after cassette administration appeared to be the same as when the compounds were dosed individually. ¹⁹F NMR may thus enable metabolism to be estimated for several compounds simultaneously, with minimal sample preparation, and without interference from endogenous molecules in the biofluid. This analytical approach may therefore be of value at the drug discovery stage in the development of ‘high throughput’ in vivo metabolic screens.

References

1. J. R. Everett, K. Jennings and G. J. Woodnut, Pharm. Pharmacol., 1985, 37, 869.
2. P. J. Gilbert, T. E. Hartley, J. A. Troke, R. G. Turcan, C. W. Vose and K. V. Watson, Xenobiotica, 1992, 22, 775.
3. M. E. Bollard, E. H. Holmes, C. A. Blackledge, J. C. Lindon, I. D. Wilson and J. K. Nicholson, Xenobiotica, 1996, 26, 255.
4. B. C. Sweatman, R. D. Farrant, P. N. Sanderson, I. Phillipe, S. R. Salman, J. K. Nicholson and J. C. Lindon, J. Magn. Reson. Anal., 1995, 1, 9.
5. N. Wu, T. L. Peck, A. G. Webb, R. L. Magin and J. V. Sweedler, Anal. Chem., 1994, 66, 3849.
6. J. Schewitz, P. Gfrörer, K. Pusecker, L.-H. Tseng, K. Albert, E. Bayer, I. D. Wilson, N. J. Bailey, G. B. Scarfe, J. K. Nicholson and J. C. Lindon, Analyst, 1998, 123, 2835.
7. W. Potts, D. Lundberg, J. Peters, H. Bi, G. Stelman and P. Sandhu, International Society for the Study of Xenobiotics Proceedings, 1995, 8, 404.
8. L. W. Frick, K. K. Adkison, K. J. Wellsknecht, P. Woollard and D. M. Higton, Pharm. Sci. Technol. Today, 1998, 1, 12.
9. M. H. Tarbit and J. Berman, Curr. Opin. Chem. Biol., 1988, 2, 411.
10. J. Berman, K. Halm, K. Adkison and J. J. Shaffer, J. Med. Chem., 1997, 40, 827.
11. F. Y. K. Ghauri, C. A. Blackledge, I. D. Wilson and J. K. Nicholson, J. Pharm. Biomed. Anal., 1990, 8, 939.
12. G. B. Scarfe, B. Wright, E. Clayton, S. Taylor, I. D. Wilson, J. C. Lindon and J. K. Nicholson, Xenobiotica, 1998, 28, 373.
13. M. Tugnait, PhD Thesis, University of London, 1994.
14. J. P. Shockor, S. H. Unger, I. D. Wilson, P. J. D. Foxall, J. K. Nicholson and J. C. Lindon, Anal. Chem., 1996, 68, 4431.
15. M. Spraul, M. Hofmann, M. Ackermann, A. W. Nicholls, S. J. P. Damment, J. N. Haselden, J. P. Shockcor, J. K. Nicholson and J. C. Lindon, Anal. Commun., 1997, 34, 339.