Abstract

Sitagliptin (STG), a drug for treating Type Ii Diabetes Mellitus (T2DM), has been associated with severe joint pain in some patients. In this paper the metabolic profile of the drug has been investigated in order to determine metabolism and formation of reactive compounds which may contribute to this adverse effect. Metabolism of STG was investigated in vitro by incubation with freshly isolated Sprague-Dawley rat hepatocytes, to characterize Phase I and II metabolites, and the reaction mixture analysed on a zwitter ionic hydrophilic interaction (ZIC®-HILIC) column using LC-MS and LC-MS2 utilising electrospray ionization (ESI) in the positive ion mode. STG was metabolised to yield eleven metabolites, but in total only 3.1% of the parent drug was metabolised over 2 hrs incubation. These metabolites were structurally characterized on the basis of accurate mass analyses and the major metabolic routes for STG determined to be via aromatic oxidation (0.86%) and desaturation of N-C and C-C of the piperazine (0.44%). Novel metabolites of STG detected using these methods included STG N-glucuronide (M6) and a di-ketone metabolite (M4), hydroxylation of both the amine group and aromatic ring followed by formation of glucuronide metabolites (M5, M5’), oxidative desaturation of NH2 and di-hydroxylation of metabolites followed by loss of HF. Also, observed was an N-sulfate metabolite (0.07%) and acetylation followed by glucuronide conjugation was also found in trace amounts (<0.01%). MS2 fragment ions provide additional structural confirmation providing a possible structure for most metabolites such as by fragment ion loss of the glucuronide group (176 Da) from metabolite M5 and loss of the phenolic sulfate (80 Da) of N-Sulfate metabolite (M7). Reduction reaction of piperazine ring probably generates highly electrophilic metabolite of STG, which may be susceptible to produce adverse effects. Furthermore, N-oxidation reaction forming reactive intermediates metabolic to give a hydroxylamine metabolite that may undergo further reactions to yield electrophilic intermediate metabolites.

Highlights

  • Diabetes mellitus is a disorder of metabolism, which is a major public health problem in all parts of the world, and recently the World Health Organization suggested that in all parts of the world almost 3 million deaths annually can be attributed to diabetes

  • Within 10 years, it is expected that about 333 million people world-wide will suffer from diabetes mellitus; with Type 2 Diabetes Mellitus (T2DM) representing about 90-95% of cases diagnosed [1]

  • The Food and Drug Administration (FDA) agreed to the sitagliptin/metformin (JanumetTM, Merck & Co.) combination in April 2007 as an assistive treatment in combination with diet and exercise to improve control of blood sugar in adult patients suffering from T2DM [3,4,5]

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Summary

Introduction

Diabetes mellitus is a disorder of metabolism, which is a major public health problem in all parts of the world, and recently the World Health Organization suggested that in all parts of the world almost 3 million deaths annually can be attributed to diabetes. Vincent et al recently reported the phase I and II metabolism of [14C] STG and six metabolites at trace levels in human plasma, urine and faeces using LC-MS2 and radiometric detection using the TurboIonSpray interface operated in the positive ion mode.

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