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Mouse pharmacokinetics and metabolism of the phenylurea thiocarbamate NSC 161128

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Abstract

Purpose

NSC 161128, a phenylurea thiocarbamate, displays activity against the NCI60 anti-cancer cell line panel and xenograft models. The metabolite N-methyl-N′-phenylurea (M10) has been detected in animal plasma; however, detection and quantification of other putative NSC 161128 metabolites have not been undertaken. The purpose of this study was to characterize the pharmacokinetics and metabolism of NSC 161128 in mice and under in vitro conditions.

Methods

An LC–MS/MS assay was developed to evaluate stability and in vitro metabolism of NSC 161128 in liver microsomes and S9 fractions. Single-dose pharmacokinetic profiles for NSC 161128 and its metabolite M10 were obtained following intraperitoneal (I.P.) administration.

Results

A sensitive and specific positive ionization LC–MS/MS method for measuring NSC 161128 and its metabolites was developed. HPLC separation was achieved under gradient elution using an aqueous methanol mobile phase containing 0.05% formic acid and 0.05% ammonium hydroxide. The assay was linear over the range 1.0–1000 ng/mL. NSC 161128 was stable in aqueous solution and tissue culture media, but not in plasma, where rapid degradation of NSC 161128 to the metabolite M10 was observed. Following I.P. administration of a 200 mg/kg dose to male CD1 mice, the peak plasma concentration of NSC 161128 was 255 ng/mL after 5 min with a plasma half-life of 138 min. Potential bioactivation of NSC 161128 was explored using mouse S9.

Conclusions

An analytical LC–MS/MS method was successfully developed for the detection and quantification of NSC 161128 and its metabolites. These results increase the understanding of NSC 161128 pharmacokinetic and metabolic properties.

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Data and/or code availability

The data that support the findings of this study are available from the corresponding author, (J.M.R), upon reasonable request.

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Acknowledgements

This project was supported in part with federal funds from the National Cancer Institute, National Institute of Health, under Contract Number N01-CM-2011-0014. The project was also funded in part by the Mayo Clinic Cancer Center Support Grant Number P30 CA15083.

Funding

This project was supported in part with federal funds from the National Cancer Institute, National Institute of Health, under Contract Number N01-CM-2011-0014. The project was also funded in part by the Mayo Clinic Cancer Center Support Grant Number P30 CA15083.

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Authors and Affiliations

  1. Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA

    Emily J. Koubek, Chad A. Walden, Renee M. McGovern, Matthew M. Ames & Joel M. Reid

  2. Nuventra Pharma Sciences, Durham, NC, 27713, USA

    Rachel A. Kudgus

  3. Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20850, USA

    Joseph M. Covey

Authors
  1. Emily J. Koubek
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  2. Rachel A. Kudgus
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  6. Matthew M. Ames
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Contributions

The authors confirm contribution to the paper as follows: study conception and design: RAK, JMC, MMA, and JMR; data collection: RAK, CAW, RMM; analysis and interpretation of results: EJK, RAK, JMC, MMA, and JMR; draft manuscript preparation: EJK. All authors reviewed the results and approved the final version of the manuscript.

Corresponding author

Correspondence to Joel M. Reid.

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Conflict of interest

R.A.K. is currently employed by Nuventra Pharma Sciences, but at the time of the study was a research fellow at Mayo Clinic. The other authors have no conflict of interest related to the conduct of this study to disclose.

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All applicable international, national, and/or institutional guidelines for the care and use animals were followed.

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Koubek, E.J., Kudgus, R.A., Walden, C.A. et al. Mouse pharmacokinetics and metabolism of the phenylurea thiocarbamate NSC 161128. Cancer Chemother Pharmacol 90, 161–174 (2022). https://doi.org/10.1007/s00280-022-04440-4

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  • DOI: https://doi.org/10.1007/s00280-022-04440-4

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