Rapid determination of polyethoxylated tallow amine surfactants in human plasma by LC-MSMS.

The potential exposure to the widely used glyphosate-based herbicides, including attempted suicide by ingestion, is of world-wide concern. Whilst the major focus to date has been on managing exposure to the active ingredient glyphosate, it is now recognised that a common major 'inert' surfactant ingredient, polyethoxylated tallow amine (POEA) and related compounds, may be more toxic. However, the information on the toxicokinetics of POEA surfactants after exposure is limited, in part, due to the lack of suitable methods for their analysis in biological matrices. We therefore developed and validated a robust LC-MSMS method that allowed, for the first time, a rapid analysis of 11 POEA homologues in human plasma. Chromatographic separation was achieved on a Kinetex EVO C18 column under a 5 min gradient elution with mobile phase A containing water/acetonitrile/formic acid (95:5:0.1, v/v/v) and mobile phase B containing acetonitrile/water/formic acid (95:5:0.1, v/v/v). Amlodipine was chosen as the internal standard (IS) for this assay. Amlodipine-d4 would be an ideal alternative IS to expand the applicability of the established method especially in antihypertensive patients. Multiple reaction monitoring (MRM) methods were optimized for 11 POEA homologues and the IS. Sample pre-treatment was performed using simple protein precipitation with methanol at a ratio of 4:1, requiring only 20 µL plasma. The validated method showed good specificity, accuracy and precision with lower limits of quantification (LLOQ) ranging from 0.35 to 10.8 ng mL-1 for all selected POEA homologues. The method was then used to measure concentrations of the various POEA surfactants in more than 600 human plasma samples from 151 patients admitted to hospital with acute glyphosate intoxication. The highest concentrations ranged from 1.07 ng mL-1 for C18u(EO)4-362.70 ng mL-1 for C16s(EO)2. The analysis of POEA surfactants plasma concentrations as described here underpins the assessment of POEA internal exposure and the relationships between POEA related glyphosate toxicity and the extent of poisoning.

[Arsenic speciation in rat plasma after oral administration of realgar and Niu Huang Jie Du Pian].

The arsenic species in rat plasma were studied after oral administration of realgar and Niu Huang Jie Du Pian (NHJDP) and the possible compatible effects of realgar was evaluated by comparing the pharmacokinetics of arsenic species after administration of realgar and NHJDP. The separation of the arsenicals was performed by a high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) technique. Dimethylarsinic acid (DMA) was found to be the main species in rats' plasma after dosing. No traces of arsenite [As(Ⅲ)], monomethylarsonic acid (MMA) or arsenate [As(Ⅴ)] were detected at any sampling time points. Compared with realgar administration alone, dose-normalized peak concentration(C(max)) and AUC(0-t) of DMA were significantly decreased by NHJDP administration, while the t(max) was significantly delayed with the clearance and apparent volume of distribution significantly increased, indicating that the pharmacokinetics of As from realgar was affected by other ingredients in the compound prescription of NHJDP.

LC-MS-MS determination of imatinib and N-desmethyl imatinib in human plasma.

A specific and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometric method was developed for the quantification of imatinib and its primary metabolite N-desmethyl imatinib in human plasma. Protein precipitation with methanol was used for sample preparation. High-performance liquid chromatographic separation was performed on a Thermo BDS Hypersil C18 column (4.6 × 100 mm, 2.4 µm) with methanol-water (55:45, v/v) containing 0.1% formic acid and 0.2% ammonium acetate as the mobile phase, using isocratic elution at a flow rate of 0.7 mL/min. Detection was conducted with positive electrospray ionization multiple reaction monitoring of the ion transitions at m/z 494 → 394 for imatinib, 480 → 394 for N-desmethyl imatinib and 297 → 110 for the internal standard (palonosetron). The assay was validated in the concentration ranges of 8-5,000 ng/mL for imatinib and 3-700 ng/mL for N-desmethyl imatinib. The quantification limits for imatinib and N-desmethyl imatinib were 8 and 3 ng/mL, respectively. The intra-day and inter-day precision values of the assay (expressed as percentage relative standard deviation) were less than 15% at all concentration levels within the tested range, and the accuracy values were between 85 and 115%. The established method was successfully applied to the pharmacokinetic study of imatinib mesylate capsules in 24 healthy Chinese volunteers.

Liquid chromatography-hydride generation-atomic fluorescence spectrometry determination of arsenic species in dog plasma and its application to a pharmacokinetic study after oral administration of Realgar and Niu Huang Jie Du Pian.

A high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) method was developed for the simultaneous determination of four arsenic species (As(III), dimethylarsinic acid (DMA), monomethylarsonic acid (MMA) and arsenate As(V)) in dog plasma. Good separation of the four arsenic species was achieved within 15min on an anion-exchange column with isocratic elution using 15mmol/L KH(2)PO(4) (pH 5.9) as eluent at a flow rate of 1.0mL/min. The assay was linear over the range of 1.25-200, 1.56-200, 1.34-172, and 2.50-200ng/mL with the detection limits of 0.80, 1.00, 0.86 and 2.00ng/mL for As(III), DMA, MMA and As(V), respectively. The method was validated for selectivity, precision, accuracy and recovery and then applied to a comparative pharmacokinetic study of the arsenic species in beagle dogs after a single oral administration of Realgar (24.32mg/kg, equivalent to 11.31mgAs/kg) alone or Niu Huang Jie Du Pian (a patent traditional Chinese medicine (TCM), 380mg/kg, equivalent to 28.45mgAs/kg), respectively. DMA was found to be the predominant species in the dog plasma after dosing, with As(V) appeared as the quickly eliminating one. No traces of MMA and As(III) were detected at any sampling time points. The main pharmacokinetic parameters found for DMA p.o. administration of Realgar and Niu Huang Jie Du Pian were as follows: C(max) (14.7±4.2) and (57.0±32.0)ng/mL, T(max) (2.4±0.5) and (2.5±0.5)h, AUC(0-36) (151.1±12.9) and (635.9±418.2)ngh/mL, AUC(0-∞) (206.0±44.5) and (687.2±425.1)ngh/mL, t(1/2) (16.2±7.9) and (9.4±2.2)h, respectively. The influence of compounding in Niu Huang Jie Du Pian on the pharmacokinetics of arsenics was shown with increased transformation of DMA and its faster elimination rate.