Abstract
This review highlights the novel biotransformations and rearrangement of laromustine, which is a sulfonylhydrazine alkylating agent. When incubated with rat, dog, monkey and human liver microsomes, [14C]laromustine was converted to eight radioactive components (C-1 to C-8). There was little difference in the metabolite profile among the species examined, partly because the formation of most components did not require nicotinamide adenine dinucleotide phosphate (NADPH), but involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Metabolism studies of laromustine utilizing liquid chromatography-multi-stage mass spectrometry (LC-MSn), produced a unique mass spectral rearrangement by collision-induced dissociation. From accurate mass measurements performed with a Fourier-transform ion cyclotron resonance mass spectrometer (FTICR-MS) to determine the elemental compositions of the fragments, it was speculated that laromustine undergoes rearrangement. The results suggested the loss of nitrogen (N2), methylsulfonyl and methyl isocyanate moieties from laromustine by collision-induced dissociation. The rearrangement, metabolite/decomposition products and phase II conjugations were analyzed utilizing hydrogen-deuterium exchange (H-D), exact mass, 13C-labeled laromustine, nuclear magnetic resonance spectroscopy (NMR) and LC-MSn experiments to assist with the assignments of these fragments and possible mechanistic rearrangement. The results of this study suggest that (1) P450 plays a role in C-7 formation but plays little or no role in the conversion of [14C]laromustine to C-1 through C-6 and C-8; (2) the relative abundance of individual degradation/metabolite products was not species dependent; and (3) laromustine produces several reactive intermediates that may play a role in toxicities seen in the clinical trials.
- The American Society for Pharmacology and Experimental Therapeutics