Bio-activation of drugs leading to reactive metabolites is now the major impeding factor in drug development. This has led to drug attrition as well as late stage compound failure during drug development.  Idiosyncratic drug toxicities due to reactive metabolites have even resulted in withdrawal of drugs that had been on the market such as troglitazone and amodiaquine. With the emergence of a large pool of lead compounds from computational chemistry and synthetic organic chemists, early drug screening is necessary in order to weed out unsuitable compounds for further development.  This also means efficient, cheap and fast techniques are being sought.  In our lab we have started using electrochemistry coupled to HPLC and Mass spectrometer (EC-HPLC-MS/MS)  as a tool for mimicry of oxidative metabolism and subsequent high throughput  screening of metabolites.  The ability of electrochemical techniques to mimic some of  both Phase I and Phase II oxidation reactions that are catalyzed by CYP 450 enzymes makes it a suitable and complementary technique for in vitro experiments during drug discovery and development. The absence and hence non- interference of biological matrix which characterize the hepatocellular fractions makes EC-HPLC-MS/MS a convenient tool for screening those reactive metabolites that bind to hepatocellular matrix possible. In this paper we demonstrate the utility of EC-MS/MS, in oxidation of different drugs. By definition, reactive metabolites have a very short life-time. These short-lived metabolites were trapped with glutathione or methoxyalamine and the stable adducts obtained were analyzed either directly online as well as offline using ESI-MS. Our results showed that most oxidation processes that are initiated by one electron transfer and hydrogen abstraction can be mimicked using the above method. Although slight variations were observed, most metabolites generated using EC-MS were comparable to those from perfused organs in vitro.Key words electrochemistry, oxidation,  metabolites,

Electrochemistry-HPLC-ESI-MS in mimicry of oxidative drug metabolism

248th National Meeting (2014)

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