A private testing laboratory reported in a Citizen Petition (CP) to FDA that 16 of 38 metformin drug products they tested had N-nitrosodimethyl amine (NDMA) amounts above the allowable intake (AI) of 96 ng/day. Because the FDA had been monitoring drugs for nitrosamines, orthogonal analytical procedures had been developed, validated and applied to detect the following nitrosamines in metformin drug products (if present): (i) NDMA (with a dedicated method) or (ii) NDMA (with a second confirmatory method), Nnitroso-diethylamine (NDEA), N-ethyl-N-nitroso-2-propanamine (NEIPA), N-nitrosodiisopropylamine (NDIPA), N-nitroso-din -propylamine (NDPA), N-nitrosomethylphenylamine (NMPA), N-nitroso-din -butylamine (NDBA) and N-nitroso-N-methyl-4-aminobutyric acid (NMBA). In contrast to the private laboratory results, FDA testing on the same set of 38 samples with orthogonal procedures observed amounts over the AI in only 8 of the 38 products and generally observed lower values than reported by the private testing laboratory. As described here, the investigation into the cause of the discrepancy revealed that N,N-dimethylformamide (DMF) can interfere with NDMA measurements. The data showed that the use of sufficient mass accuracy in the data acquisition and appropriate mass tolerance setting in the data processing to assure the selectivity of mass spectrometry measurements of NDMA in the presence of co-eluting DMF was necessary to prevent overestimation of the level of NDMA in metformin drug products. Overall, care should be taken to assure the necessary specificity in analytical procedures for adequate assessment of the nitrosamine level in drug products that also contain DMF or other potential interfering substances.

IMPORTANCE A publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies.OBJECTIVE To characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels. DESIGN, SETTING, AND PARTICIPANTS One 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 μmol/L) to higher concentrations (10 000 μmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method. MAIN OUTCOMES AND MEASURESNDMA detected in simulated gastric fluid 2 hours after adding ranitidine.RESULTS At a supraphysiologic nitrite concentration (ie, 10 000 μmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 μmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 μmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 μmol/L) or 10-fold physiologic (1000 μmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 μmol/L). CONCLUSIONS AND RELEVANCEIn this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 μmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.

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Accurate measurement of glomerular filtration rate (GFR) at the bedside is highly desirable in order to assess renal function in real-time, which is currently an unmet clinical need. In our pursuit to develop exogenous fluorescent tracers as GFR markers, various hydrophilic derivatives of 3,6-diaminopyrazine-2,5-dicarboxylic acid with varying molecular weights and absorption/emission characteristics were synthesized. These include polyhydroxyalkyl based small molecules and poly(ethylene glycol) (PEG) substituted moderate molecular weight compounds, which were further subgrouped into analogs having blue excitation with green emission, and relatively longer wavelength analogs having green excitation with orange emission. Lead compounds were identified in each of the four classes on the basis of structureactivity relationship studies, which included in vitro plasma protein binding, in vivo urine recovery of administered dose, and in vivo optical monitoring. The in vivo optical monitoring experiments with lead candidates have been correlated with plasma pharmacokinetic (PK) data for measurement of clearance and hence GFR. Renal clearance of these compounds, occurring exclusively via glomerular filtration, was established by probenecid blocking experiments. The renal clearance property of all these advanced candidates was superior to that of the iothalamate, which is currently an accepted standard for the measurement of GFR.