Mouse pharmacokinetics and metabolism of the phenylurea thiocarbamate NSC 161128.

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.

• Authors: Emily J Koubek, Rachel A Kudgus, Chad A Walden, Renee M McGovern, Joseph M Covey, Matthew M Ames, Joel M Reid
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 90 Issue 2 Pg. 161-174 (08 2022) ISSN: 1432-0843 [Electronic] Germany
• PMID: 35896839 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Thiocarbamates

Topics

• Animals
• Chromatography, High Pressure Liquid (methods)
• Chromatography, Liquid (methods)
• Half-Life
• Humans
• Male
• Mice
• Reproducibility of Results
• Tandem Mass Spectrometry (methods)
• Thiocarbamates