Abstract
Laromustine (VNP40101M, also known as Cloretazine) is a novel sulfonylhydrazine alkylating (anticancer) agent. Laromustine generates two types of reactive intermediates: 90CE and methylisocyanate. When incubated with rat, dog, monkey, and human liver microsomes, [14C]laromustine was converted to 90CE (C-8) and seven other radioactive components (C-1–C-7). There was little difference in the metabolite profile among the species examined, in part because the formation of most components (C-1–C-6 and 90CE) did not require NADPH but involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Laromustine caused direct inhibition of CYP2B6 and CYP3A4/5 (the two enzymes involved in C-7 formation) as well as of CYP2C19. Ki values were 125 μM for CYP2B6, 297 μM for CYP3A4/5, and 349 μM for CYP2C19 and were greater than the average clinical plasma Cmax of laromustine (25 μM). There was evidence of time-dependent inhibition of CYP1A2, CYP2B6, and CYP3A4/5. Treatment of primary cultures of human hepatocytes with up to 100 μM laromustine did not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, but the highest concentration of laromustine decreased the activity and levels of immunoreactive CYP3A4. The results of this study suggest the laromustine has 1) negligible victim potential with respect to metabolism by cytochrome P450 enzymes, 2) negligible enzyme-inducing potential, and 3) the potential in some cases to cause inhibition of CYP2B6, CYP3A4, and possibly CYP2C19 during and shortly after the duration of intravenous administration of this anticancer drug, but the clinical effects of such interactions are likely to be insignificant.
Footnotes
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This work was supported by Vion Pharmaceuticals, Inc., New Haven, CT.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.027516.
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ABBREVIATIONS: VNP40101M, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine, laromustine, also known as Cloretazine; 90CE, a pharmacologically active degradation product of laromustine (as VNP4090CE and, in this study, C-8); AGT, O6-alkylguanine-DNA-alkyltransferase; FDA, Food and Drug Administration; P450, cytochrome P450; FMO, flavin-containing monooxygenase; DMSO, dimethyl sulfoxide; HPLC, high-performance liquid chromatography; r, recombinant; C-7, VNP40107 (a metabolite of laromustine); ANOVA, analysis of variance.
- Accepted April 8, 2009.
- Received March 10, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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