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Distinguishing a phosphate ester prodrug from its isobaric sulfate metabolite by mass spectrometry without the metabolite standard.

A phosphate prodrug of a phenolic or alcoholic drug is isobaric with the putative sulfate metabolite of the drug. During liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis of biological samples obtained after the administration of a phosphate prodrug, a product ion arising from the parent drug portion of the prodrug molecule is commonly used in selected reaction monitoring (SRM) utilized for the simultaneous quantitation of the prodrug and the in vivo generated parent drug. While the advantage of using a drug moiety-specific LC-SRM method is obvious, one drawback is that the sulfate metabolite will also respond to such an SRM transition since the metabolite will invariably yield the same product ion as the prodrug. Thus, the sulfate metabolite could be mistaken for the prodrug unless chromatographic separation between the two is achieved. In the absence of a reference standard for the sulfate metabolite to demonstrate chromatographic separation, it is important to establish a procedure that can ascertain the absence of the sulfate metabolite in the study samples to ensure the specificity of the method for the prodrug. To this end, we studied the MS/MS behavior of model phosphate and sulfate ester compounds and developed a procedure based on phosphate-specific and sulfate-specific product ions for distinguishing the phosphate prodrug from the sulfate metabolite.