Determination of the metabolites of pesticides formed in soil, plants and livestock is important in determining potential human dietary uptake and environmental impact. Metabolites of investigational drugs similarly need examination to assess toxicological risk and study the potential for drug-drug interactions. Liquid chromatography – tandem mass spectrometry (HPLC-MS/MS) technology is the front-line method for estimating the structures of metabolites, however this technique can be hampered by the complexity of background matrices which contain the metabolites to be examined, e.g. extracts of soil, plants, faeces etc. Such problems can be exacerbated when metabolites are present in very low concentration. Furthermore, MS/MS is sometimes unable to unequivocally distinguish between regio-isomers, and both of these limitations can lead to a situation of speculative chemical synthesis where several possible structures are made by trial and error in order to access the correct metabolite for identification and, where appropriate to provide material for biological testing. To complicate the picture still further, regio- and stereo-selective <i>de novo </i>chemical synthesis of drug and agrochemical metabolites is generally not simple, and in some cases, impossible. Fortunately, several methods are available to produce metabolites in a “late-stage” manner, i.e. where the parent agrochemical (or pharmaceutical) is subjected to multiple biotransformation techniques involving enzymes, liver fractions as well as bacteria and fungi, to effect the necessary chemical change to produce metabolites. Late-stage chemical oxidations and conjugations (e.g. glucuronidation) can also provide a successful route to target metabolites.  This presentation will use case studies to illustrate the utility of these techniques to produce metabolites of drugs and agrochemicals, and will include aspects of structure elucidation by NMR, a technique which has developed significantly in recent years, to the extent that only low microgram amounts of metabolites are required for definitive structure identification.

Comprehensive solutions for accessing metabolites of drugs and agrochemicals

ACS Fall 2021

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