Identification of Novel Metabolic Pathways of Sitagliptin (STG) by LC/MS and LC/MS2 after Incubations with Rat Hepatocytes

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

THE TREND TOWARDS IMPLEMENTING THE PRECAUTIONARY PRINCIPLE IN US REGULATION OF NANOMATERIALS

The precautionary principle provides a framework for regulating emerging technologies in general and nanomaterials in particular. It counsels action in the presence of uncertainties about risk instead of assuming that nanomaterials are safe unless proven hazardous. Nanomaterials are regulated under different statutory programs depending on whether they are drugs, pesticides or other commercial chemicals. Recent developments in the regulation of nanomaterials that are not drugs or pesticides have demonstrated a trend towards application of the precautionary principle. This is a paradigm shift away from the requirement built into past interpretations of the Toxic Substances Control Act (“TSCA”) that manufacturing, processing and use of chemical substances cannot be restricted unless the regulatory authority proves an unreasonable risk. This same paradigm shift is incorporated into recent legislative proposals to amend TSCA

Explosive growth of facet joint interventions in the medicare population in the United States: a comparative evaluation of 1997, 2002, and 2006 data

<p>Abstract</p> <p>Background</p> <p>The Office of Inspector General of the Department of Health and Human Services (OIG-DHHS) issued a report which showed explosive growth and also raised questions of lack of medical necessity and/or indications for facet joint injection services in 2006.</p> <p>The purpose of the study was to determine trends of frequency and cost of facet joint interventions in managing spinal pain.</p> <p>Methods</p> <p>This analysis was performed to determine trends of frequency and cost of facet joint</p> <p>Interventions in managing spinal pain, utilizing the annual 5% national sample of the Centers for</p> <p>Medicare and Medicaid Services (CMS) for 1997, 2002, and 2006.</p> <p>Outcome measures included overall characteristics of Medicare beneficiaries receiving facet joint interventions, utilization of facet joint interventions by place of service, by specialty, reimbursement characteristics, and other variables.</p> <p>Results</p> <p>From 1997 to 2006, the number of patients receiving facet joint interventions per 100,000</p> <p>Medicare population increased 386%, facet joint visits increased 446%, and facet joint interventions increased 543%. The increases were higher in patients aged less than 65 years compared to those 65 or older with patients increasing 504% vs. 355%, visits increasing 587% vs. 404%, and services increasing 683% vs. 498%.</p> <p>Total expenditures for facet joint interventions in the Medicare population increased from over $229 million in 2002 to over$511 million in 2006, with an overall increase of 123%. In 2006, there was a 26.8-fold difference in utilization of facet joint intervention services in Florida compared to the state with the lowest utilization - Hawaii.</p> <p>There was an annual increase of 277.3% in the utilization of facet joint interventions by general physicians, whereas a 99.5% annual increase was seen for nurse practitioners (NPs) and certified registered nurse anesthetists (CRNAs) from 2002 to 2006. Further, in Florida, 47% of facet joint interventions were performed by general physicians.</p> <p>Conclusions</p> <p>The reported explosive growth of facet joint interventions in managing spinal pain in certain regions and by certain specialties may result in increased regulations and scrutiny with reduced access.</p