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Characterisation of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity

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Summary

The experimental antineoplastic agent temozolomide was not metabolised in vitro at a measurable rate by mouse liver fractions. In contrast, the temozolomide analogue 3-methylbenzotriazinone was metabolicallyN-demethylated by hepatic microsomes to yield benzotriazinone. The major route of excretion of [14C]-labelled temozolomide in mice was via the kidneys. An acidic metabolite of temozolomide, probably a conjugate, was found in the urine of mice, but its identity could not be established unambiguously. Spectroscopic analysis and chemical tests revealed that it possesses an intact NNN-linkage. Another metabolite was found in the urine of patients but not of mice. This metabolite was identified as the 8-carboxylic acid derivative of temozolomide. Unlike the unknown species, this metabolite was cytotoxic against TLX5 lymphoma cells in vitro.

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Authors and Affiliations

  1. Medical Research Council Toxicology Unit, Woodmasterne Road, Carshalton, Surrey, England

    Peter B. Farmer

  2. CRC Experimental Chemotherapy Group, Pharmaceutical Sciences Institute, Aston University, Aston Triangle, B4 7ET, Birmingham, U.K.

    Lincoln L. H. Tsang, Andreas Gescher & John A. Slack

Authors
  1. Lincoln L. H. Tsang
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  2. Peter B. Farmer
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  3. Andreas Gescher
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  4. John A. Slack
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Additional information

Part XXII in the series “Antineoplastic imidazotetrazines”; for part XXI see [4]

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Tsang, L.L.H., Farmer, P.B., Gescher, A. et al. Characterisation of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity. Cancer Chemother Pharmacol 26, 429–436 (1990). https://doi.org/10.1007/BF02994094

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  • DOI: https://doi.org/10.1007/BF02994094

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