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Pharmacokinetics and mechanism of action of detoxifying low-molecular-weight thiols

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Summary

A number of thiol compounds have been studied with reference to their selective protective action against urotoxic side-effects of oxazaphosphorine cytostatics. The uroprotective capacity is determined exclusively by the pharmacokinetic behavior of the compound. When given PO, all compounds tested were absorbable from the gut. Both thiols and disulfides are rapidly eliminated from the blood, but during their short half-life a number of unknown chemical reactions probably take place to maintain a physiological redox equilibrium.

Elimination from the blood plasma occurs via two fundamentally different mechanisms: by distribution throughout the tissue and intracellular uptake or, alternatively, by rapid renal excretion. Most of the compounds tested belong to the first group: N-acetylcysteine, carboxycysteine, disulfiram and its metabolite DDTC, glutathione, WR 2721, etc. Few compounds are quantitatively excreted through the urine: mesna, dimesna, and DA 12. Only these compounds were suitable for selective regional detoxification and for the prevention of oxazaphosphorine-induced urotoxic lesions.

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Authors and Affiliations

  1. Department of Experimental Cancer Research, Asta-Werke AG, Degussa Pharma Gruppe, D-4800, Bielefeld 14, Federal Republic of Germany

    N. Brock, P. Hilgard & J. Pohl

  2. Department of Forensic Medicine, Karolinska Institutet, Box 60400, S-10401, Stockholm, Sweden

    K. Ormstad & S. Orrenius

Authors
  1. N. Brock
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  2. P. Hilgard
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  3. J. Pohl
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  4. K. Ormstad
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  5. S. Orrenius
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Additional information

Dedicated to Professor Hermann Druckrey on the occasion of his 80th birthday.

This work was conducted under a Swedish-German agreement on biotechnological cooperation and was funded by the Swedish National Board for Technical Development and by the German Federal Ministry of Research and Technology

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Brock, N., Hilgard, P., Pohl, J. et al. Pharmacokinetics and mechanism of action of detoxifying low-molecular-weight thiols. J Cancer Res Clin Oncol 108, 87–97 (1984). https://doi.org/10.1007/BF00390979

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  • DOI: https://doi.org/10.1007/BF00390979

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