RESUMO
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.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dexmedetomidina/sangue , Dexmedetomidina/farmacocinética , Espectrometria de Massas em Tandem/métodos , Acetonitrilas/química , Química Farmacêutica/métodos , Estabilidade de Medicamentos , Feminino , Formiatos/química , Humanos , Íons , Masculino , Modelos Químicos , Ondansetron/análise , Ondansetron/sangue , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodosRESUMO
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.
Assuntos
Acetaminofen/sangue , Amantadina/sangue , Analgésicos não Narcóticos/sangue , Cafeína/sangue , Estimulantes do Sistema Nervoso Central/sangue , Clorfeniramina/sangue , Antagonistas dos Receptores Histamínicos H1/sangue , Acetaminofen/farmacocinética , Amantadina/farmacocinética , Analgésicos não Narcóticos/farmacocinética , Cafeína/farmacocinética , Estimulantes do Sistema Nervoso Central/farmacocinética , Clorfeniramina/farmacocinética , Cromatografia Líquida de Alta Pressão , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Humanos , Masculino , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em TandemRESUMO
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.
Assuntos
Nootrópicos/farmacologia , Nootrópicos/farmacocinética , Pirrolidinonas/farmacologia , Pirrolidinonas/farmacocinética , Análise de Variância , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica , Estudos Cross-Over , Método Duplo-Cego , Meia-Vida , Humanos , Masculino , Equivalência Terapêutica , Adulto JovemRESUMO
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.