Determination of dexmedetomidine in human plasma using high performance liquid chromatography coupled with tandem mass spectrometric detection: application to a pharmacokinetic study.

A rapid, sensitive and selective high performance liquid chromatography-electrospray ionization-tandem mass spectrometry method (HPLC-ESI-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of dexmedetomidine (DMED) in human plasma. Dexmedetomidine and the internal standard (ondansetron) were extracted in a single step with diethyl-ether from 1.0 mL of alkalinized plasma. The mobile phase was a mixture of acetonitrile and 0.5% formic acid solution (30:70, v/v) at a flow rate of 0.2 mL min(-1). The detection was performed on a triple quadrupole tandem mass spectrometer in the selected reaction monitoring (SRM) mode using the respective [M+H]+ ions m/z 201.0-->95.1 for DMED and m/z 294.1-->170.1 for the IS. The assay exhibited a linear dynamic range of 5-5000 pg mL(-1) with the correlation coefficient above 0.9995. The lower limit of quantification (LLOQ) was 5 pg mL(-1) with a relative standard deviation of less than 15%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The validated HPLC-MS/MS method has been successfully applied to study the pharmacokinetics of three level doses of DMED in Chinese healthy volunteers.

Rapid simultaneous determination of paracetamol, amantadine hydrochloride, caffeine and chlorpheniramine maleate in human plasma by liquid chromatography/tandem mass spectrometry.

A rapid, simple and sensitive high performance liquid chromatography with positive ion electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was first developed and validated to simultaneously determine paracetamol (PAR, CAS 103-90-2), amantadine hydrochloride (ATH, CAS 665-66-7), caffeine (CAF, CAS 58-08-2) and chlorpheniramine maleate (CPM, CAS 113-92-8) in human plasma using tramadol hydrochloride (TMH, CAS 22204-88-2) as internal standard (IS). Following methanol-induced protein precipitation, the analytes were separated using a mobile phase comprised of methanol:water (0.5% formic acid) = 20:80 (v/v) on a commercially available column (150 mm x 2.1 mm I.D., 5 microm) and analyzed by electrospray ionization tandem mass spectrometry in the selected reaction monitoring (SRM) mode with the precursor to product ion transitions m/z 152.3-->110.2 for PAR, 152.3-->135.3 for ATH, 195.1-->138.3 for CAF, 275.2-->230.3 for CPM and 264.2-->58.2 for TMH. The standard curves were linear (r2 > 0.99) over the concentration range of 0.2-20 microg/mL for PAR, 20-2000 ng/mL for ATH and CAF, 0.1-10 ng/mL for CPM and had good accuracy and precision, respectively. The within- and between-batch precisions were less than 15% in terms of relative standard deviation (RSD). The lower limit of quantitation (LLOQ) were 0.2 microg/mL, 20 ng/mL, 20 ng/mL and 0.1 ng/mL for PAR, ATH, CAF and CPM, respectively. The described method has been successfully applied to study the pharmacokinetics of paracetamol-amantadine hydrochloride tablets in Chinese healthy male volunteers with great precision and sensitivity.

Pharmacokinetics and bioequivalence study of aniracetam after single-dose administration in healthy Chinese male volunteers.

The pharmacokinetics of aniracetam (CAS 72432-10-1) in Chinese healthy male volunteers was investigated for the first time. Twenty male volunteers were enrolled into this open, randomized, single blind two-sequence, two-period crossover study. Under fasting conditions, each subject received a single oral dose of 400 mg (2 x 200 mg/capsule) aniracetam as a test or reference formulation with a 3-day washout period between the two preparations. The plasma concentrations of aniracetam were analyzed by a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The pharmacokinetic parameters of the test and reference formulations were estimated as follows: The maximum plasma concentrations (Cmax) were 8.75 +/- 7.82 and 8.65 +/- 8.70 ng/mL, Tmax were 0.4 +/- 0.1 and 0.4 +/- 0.1 h, and plasma elimination half-lives (t(1/2)) were 0.47 +/- 0.16 and 0.49 +/- 0.24 h, respectively. The AUC(0-t) values demonstrated nearly identical bioavailability of aniracetam from the examined formulations. AUC(0-2.5) values were 4.53 +/- 6.62 and 4.76 +/- 6.65 ng h/mL, the areas under the plasma concentration-time curve (AUC(0-infinity) were 4.62 +/- 6.66 and 4.85 +/- 6.71 ng h/mL for the test and reference formulation, respectively. No statistical differences were observed for Cmax, and AUC(0-infinity) for aniracetam. The 90% confidence limits calculated for AUC and Cmax of aniracetam were within the standard bioequivalence range (80%-125% for AUC and Cmax). Therefore, the aniracetam test formulation can be regarded as bioequivalent to the aniracetam reference formulation.

High-performance liquid chromatography-electrospray ionization mass spectrometry determination of mitiglinide in human plasma and its pharmacokinetics.

A selective and sensitive method employing high-performance liquid chromatography-electrospray ionization mass spectrometry was developed and validated for the determination of mitiglinide in human plasma.With gliclazide as the internal standard, mitiglinide was extracted from plasma with n-hexane: = 80 : 20 (v/v). The organic layer was evaporated and the residue was redissolved in methanol: water (10 mM CH3COONH4, pH = 3.0) = 65 : 35 (v/v). An aliquot of 10 microl was chromatographically analyzed on a prepacked Shimadzu VP-ODS (5 microm, 150 x 2.0 mm i.d.) using the mobile phase comprising methanol: water (10 mM CH3COONH4) = 65 : 35 (v/v) by means of selected-ion monitoring mode mass spectrometry. Standard curves were linear (r2 = 0.9972) over the concentration range of 2.84-11 300 pmol/ml and had good accuracy and precision. The within- and between-batch precisions of the method were within 15% of standard deviation. The lower limit of detection was 1.42 pmol/ml. The validated HPLC/ESI-MS method has been successfully applied in the pharmacokinetics of mitiglinide in 12 healthy Chinese volunteers.