RESUMEN

BACKGROUND: To evaluate the bioequivalence between test and reference formulations of perindopril tert-butylamine under fasting and fed conditions and to assess their pharmacokinetic (PK) and safety profiles. METHOD: A randomized, open-label, single-dose, crossover trial was conducted in healthy Chinese subjects. Test or reference perindopril tert-butylamine tablets (4 mg) were randomly given to subjects under fasting (2-period crossover, with an administration sequence of test tablet (T), reference tablet (R) or RT) and fed (4-period crossover, with an administration sequence of TRTR or RTRT) conditions, while each single administration was followed by a 14-day washout period. The plasma concentrations and corresponding non-compartmental PK parameters of perindopril and perindoprilat were determined. The two formulations were considered to be bioequivalent if the 90 % confidence intervals (CIs) of the geometric mean (GM) ratio (test/reference) for Cmax, AUC0-t, and AUC0-∞ (perindopril) was both within the range of 80-125 %. Safety assessments including vital signs, physical examination, laboratory examination, 12-lead ECG and reports of treatment emergent adverse events (TEAEs) were carefully documented. RESULTS: A total of 64 subjects (32 in each trial) were randomized and all completed the trials. Regardless of fasting or fed trials, the PK characteristics of perindopril and perindoprilat for the test formulation were similar to those of the reference formulation (all P > 0.05). The 90 % CIs of the geometric mean (GM) ratio for Cmax, AUC0-t, and AUC0-∞, respectively, were 92.86-106.81 %, 98.44-102.88 % and 98.48-103.02 % under the fasting condition and 90.64-110.04 %, 96.95-101.90 % and 96.83-101.78 % under the fed condition, which were both within the pre-specified range of 80-125 %. A total of 10 (31.3 %) fasted subjects and 11 (34.4 %) fed subjects experienced 11 and 24 TEAEs, respectively, all of which were within the severity of grade 1. The incidence of TEAEs and drug-related TEAEs were similar between test and reference formulations (all P > 0.05) and no serious TEAEs or deaths occurred during the trials. CONCLUSIONS: The test and reference formulations of perindopril tert-butylamine tablets (4 mg) were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions.

Asunto(s)

Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Antihipertensivos/farmacocinética , Butilaminas/farmacocinética , Medicamentos Genéricos/farmacocinética , Perindopril/análogos & derivados , Perindopril/farmacocinética , Administración Oral , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Butilaminas/administración & dosificación , Butilaminas/efectos adversos , China , Estudios Cruzados , Composición de Medicamentos , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/efectos adversos , Ayuno/sangre , Femenino , Humanos , Masculino , Perindopril/administración & dosificación , Perindopril/efectos adversos , Periodo Posprandial , Comprimidos , Equivalencia Terapéutica , Adulto Joven

RESUMEN

PURPOSE: This study compared the bioequivalence of two formulations of escitalopram oxalate 20 mg tablets in terms of bioavailability and tolerability in healthy Chinese male and female subjects. PATIENTS AND METHODS: A randomized, single-blind, two-period, two-sequence crossover study was performed under fasting and fed conditions, with a 21-day washout period. In total, 24 healthy subjects (18 males and 6 females) were enrolled in the fasting test and the fed test, respectively. Blood samples were collected over 168 h post-dose in each period. The concentrations of escitalopram in plasma were determined by high-performance liquid chromatography coupled with a tandem mass spectrometry. Pharmacokinetic parameters used for bioequivalence assessment were determined from the drug concentration data using noncompartmental analysis. RESULTS: All subjects showed good medication compliance. The 90% confidence intervals (CIs) for the geometric mean ratios of AUC0-t, AUC0-∞, and Cmax were within the bioequivalence acceptance criteria (80.00% to 125.00%). Adverse events were recorded and no deaths or serious adverse events (SAEs) occurred. CONCLUSION: Escitalopram oxalate 20 mg tablets produced in China were bioequivalent to the reference formulation (Lexapro®) in healthy Chinese male and female subjects under fasting and fed conditions.

Asunto(s)

Citalopram/farmacocinética , Medicamentos Genéricos/farmacocinética , Ayuno , Adulto , Pueblo Asiatico , Disponibilidad Biológica , Estudios Cruzados , Composición de Medicamentos , Femenino , Interacciones Alimento-Droga , Voluntarios Sanos , Humanos , Masculino , Estructura Molecular , Comprimidos

RESUMEN

Nifekalant is a class III antiarrhythmic drug, and its major adverse effect is prolongation of the QT interval. This study analysed data generated from a pharmacokinetic (PK) study to develop a population PK/pharmacodynamics (PD) model for describing the relationship between plasma concentrations and prolongation of the QT interval over time following intravenous administration of nifekalant. This open-labelled, phase I clinical study comprised two dose level groups of eight healthy Chinese volunteers. Concentrations of nifekalant in plasma samples collected at set time-points were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. A PK/PD model was constructed using a non-linear mixed-effects approach (Phoenix NLME 8.1). Furthermore, demographic covariates of the model were investigated and a concentration factor (ConcƟ) was introduced as the only covariate which improved the performance of the model. The final population PK model exhibited one-order elimination with two-compartment distribution and adequately described nifekalant plasma concentrations over time. The QT interval prolongation was best described by an indirect effect model with an inhibition build-up effect, representing the relationship between plasma concentrations and effect. The final population PK/PD model may facilitate more accurate predictions of the drug profile in clinical settings in the future.

Asunto(s)

Modelos Biológicos , Espectrometría de Masas en Tándem , China , Cromatografía Liquida , Relación Dosis-Respuesta a Droga , Voluntarios Sanos , Humanos , Pirimidinonas

RESUMEN

BACKGROUND: Pivotal clinical trials found that ticagrelor reduced ischaemic complications to a greater extent than clopidogrel, and also that the benefit gradually increased with the reduction in creatinine clearance. However, the underlying mechanisms remains poorly explored. METHODS: This was a single-centre, prospective, randomized clinical trial involving 60 hospitalized Adenosine Diphosphate (ADP) P2Y12 receptor inhibitor-naïve patients with chronic kidney disease (CKD) (estimated glomerular filtration rate <60 ml min-1 1.73 m-2 ) and non-ST-elevation acute coronary syndromes (NSTE-ACS). Eligible patients were randomly assigned in a 1:1 ratio to receive ticagrelor (180 mg loading dose, then followed by 90 mg twice daily) or clopidogrel (600 mg loading dose, then followed by 75 mg once daily). The primary endpoint was the P2Y12 reactive unit (PRU) value assessed by VerifyNow at 30 days. The plasma concentrations of ticagrelor and clopidogrel and their active metabolites were measured in the first 10 patients in each group at baseline, and at 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after the loading dose. RESULTS: Baseline characteristics were well matched between the two groups. Our results indicated a markedly lower PRU in patients treated with ticagrelor vs. clopidogrel at 30 days (32.6 ± 11.29 vs. 203.7 ± 17.92; P < 0.001) as well as at 2 h, 8 h and 24 h after the loading dose (P < 0.001). Ticagrelor and its active metabolite AR-C124910XX showed a similar time to reach maximum concentration (Cmax ) of 8 h, with the maximum concentration (Cmax ) of 355 (242.50-522.00) ng ml-1 and 63.20 (50.80-85.15) ng ml-1 , respectively. Both clopidogrel and its active metabolite approached the Cmax at 2 h, with a similar Cmax of 8.67 (6.64-27.75) ng ml-1 vs. 8.53 (6.94-15.93) ng ml-1 . CONCLUSION: Ticagrelor showed much more potent platelet inhibition in comparison with clopidogrel in patients with CKD and NSTE-ACS.

Asunto(s)

Síndrome Coronario Agudo/tratamiento farmacológico , Adenosina/análogos & derivados , Antagonistas del Receptor Purinérgico P2Y/farmacología , Insuficiencia Renal Crónica/fisiopatología , Ticlopidina/análogos & derivados , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/complicaciones , Adenosina/sangre , Adenosina/farmacología , Adenosina/uso terapéutico , Anciano , Clopidogrel , Creatinina/sangre , Femenino , Tasa de Filtración Glomerular , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/sangre , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pruebas de Función Plaquetaria , Estudios Prospectivos , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Eliminación Renal , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Ticagrelor , Ticlopidina/sangre , Ticlopidina/farmacología , Ticlopidina/uso terapéutico , Resultado del Tratamiento

RESUMEN

AIM: This study developed a high-performance liquid chromatography-tandem mass spectrometry method to simultaneously determine the concentrations of flupirtine and its major active metabolite D-13223 in human plasma in order to assess the bioequivalence (BE) of two flupirtine maleate capsules among healthy male Chinese volunteers under fasting and fed conditions. MATERIALS AND METHODS: There were two single-center, randomized, single-dose, open-label, laboratory-blinded, two-period, cross-over studies which included 24 healthy male Chinese volunteers under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 48 h after dosing. The concentrations of flupirtine and its major active metabolite D-13223 in plasma samples were determined by a validated method, that is, high-performance liquid chromatography coupled with a tandem mass spectrometry detector. Pharmacokinetic metrics of area from time zero to the last measurable concentration (AUC0-t), area under the plasma concentration-time curve from administration to infinite time (AUC0-∞), and Cmax were used for BE assessment. RESULTS: Forty-eight healthy volunteers who met the criteria were enrolled and completed the study. According to the observation of vital signs and laboratory measurement, no volunteers had any adverse reactions. Under fasting condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 103.0% (98.1%-108.2%) for AUC0-t, 102.9% (98.2%-107.9%) for AUC0-∞, and 97.0% (85.9%-109.5%) for Cmax. Under fed condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 101.7% (98.4%-105.1%) for AUC0-t, 101.6% (98.5%-104.8%) for AUC0-∞, and 103.5% (94.7%-113.0%) for Cmax. The difference between test and reference formulations, Tmax, was not statistically significant. The 90% CIs of the test/reference AUC ratio and Cmax ratio of D-13223 were also within the acceptance range for BE both under fasting and fed conditions. CONCLUSION: The two formulations of flupirtine maleate capsule were bioequivalent (the test and the reference products) under fasting and fed conditions, and thus both can be used interchangeably in the clinical setting.

Asunto(s)

Aminopiridinas/farmacocinética , Ayuno , Maleatos/farmacocinética , Adolescente , Adulto , Aminopiridinas/administración & dosificación , Aminopiridinas/química , Cápsulas , China , Estudios Cruzados , Voluntarios Sanos , Humanos , Masculino , Maleatos/administración & dosificación , Maleatos/química , Estructura Molecular , Equivalencia Terapéutica , Adulto Joven

RESUMEN

PURPOSE: The aim of this study was to evaluate the bioequivalence of a generic product 70 mg alendronate sodium tablets with the reference product Fosamax® 70 mg tablet. MATERIALS AND METHODS: A single-center, open-label, randomized, three-period, three-sequence, reference-replicated crossover study was performed in 36 healthy Chinese male volunteers under fasting conditions. In each study period, the volunteers received a single oral dose of the generic or reference product (70 mg). Blood samples were collected at pre-dose and up to 8 h after administration. The bioequivalence of the generic product to the reference product was assessed using the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) reference-scaled average bioequivalence (RSABE) methods. RESULTS: The average maximum concentrations (Cmax) of alendronic acid were 64.78±43.76, 56.62±31.95, and 60.15±37.12 ng/mL after the single dose of the generic product and the first and second doses of the reference product, respectively. The areas under the plasma concentration-time curves from time 0 to the last timepoint (AUC0-t ) were 150.36±82.90, 148.15±85.97, and 167.11±110.87 h⋅ng/mL, respectively. Reference scaling was used because the within-subject standard deviations of the reference product (sWR ) for Cmax and AUC0-t were all higher than the cutoff value of 0.294. The 95% upper confidence bounds were -0.16 and -0.17 for Cmax and AUC0-t , respectively, and the point estimates for the generic/reference product ratio were 1.08 and 1.00, which satisfied the RSABE acceptance criteria of the FDA. The 90% CIs for Cmax and AUC0-t were 90.35%-129.04% and 85.31%-117.15%, respectively, which were within the limits of the EMA for the bioequivalence of 69.84%-143.19% and 80.00%-125.00%. CONCLUSION: The generic product was bioequivalent to the reference product in terms of the rate and extent of alendronate absorption after a single 70 mg oral dose under fasting conditions.

Asunto(s)

Alendronato/farmacología , Conservadores de la Densidad Ósea/farmacología , Adolescente , Adulto , Alendronato/efectos adversos , Área Bajo la Curva , Pueblo Asiatico , Disponibilidad Biológica , Conservadores de la Densidad Ósea/efectos adversos , Estudios Cruzados , Medicamentos Genéricos , Voluntarios Sanos , Humanos , Masculino , Equivalencia Terapéutica , Adulto Joven

RESUMEN

PURPOSE: To investigate the effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin in humans. METHODS: Two independent, open-label, randomized, crossover studies were conducted in 24 (12 per study) healthy Chinese volunteers. In Study 1, each volunteer received a single oral dose of 500 mg of nemonoxacin alone or with 1.5 g of probenecid divided into three doses within 25 hours. In Study 2, each volunteer received a single oral dose of 500 mg of nemonoxacin alone or with multiple doses of cimetidine (400 mg thrice daily for 7 days). The plasma and urine nemonoxacin concentrations were determined using validated liquid chromatography-tandem mass spectrometry methods. RESULTS: Coadministration of nemonoxacin with probenecid reduced the renal clearance (CLr) of nemonoxacin by 22.6%, and increased the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) by 26.2%. Coadministration of nemonoxacin with cimetidine reduced the CLr of nemonoxacin by 13.3% and increased AUC0-∞ by 9.4%. Coadministration of nemonoxacin with probenecid or cimetidine did not significantly affect the maximum concentration of nemonoxacin or the percentage of the administered dose recovered in the urine. CONCLUSION: Although probenecid reduced the CLr and increased the plasma exposure of nemonoxacin, these effects are unlikely to be clinically meaningful at therapeutic doses. Cimetidine had weaker, clinically meaningless effects on the pharmacokinetics of nemonoxacin.

Asunto(s)

Antibacterianos/farmacocinética , Cimetidina/farmacología , Probenecid/farmacología , Quinolonas/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Pueblo Asiatico , Cromatografía Liquida , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Espectrometría de Masas en Tándem , Adulto Joven

RESUMEN

Our paper aimed to develop rapid, sensitive, and specific LC-MS/MS method for the quantification of niacin (NA) and its metabolite nicotinuric acid (NUA) in human plasma. Following protein precipitation with acetonitrile, the NA, NUA, and internal standard (5-fluorouracil) were separated on a Zorbax 300SB-C8 column (250 mm × 4.6 mm, 5 µm) with a mobile phase consisting of methanol-2 mM ammonium acetate (3 : 97, v/v) at a flow rate of 1 mL/min (split 1 : 1). A tandem mass spectrometer equipped with electrospray ionization source was used as the detector and operated in negative ion mode. The linear concentration ranges of the calibration curves were 5-800 ng/mL for NA and NUA. The intra-assay RSD for quality control (QC) samples were from 5.0% to 8.7% for NA, and 5.5% to 7.6% for NUA. The interassay RSD for QC samples were from 2.8% to 9.4% for NA, and 3.7% to 5.8% for NUA. The relative errors for QC samples were from -2.2% to 2.3% for NA, and -0.6% to 3.2% for NUA. The method was successfully applied to the investigation of the pharmacokinetic profiles of NA, NUA in human after single dose administration of Niacin extended-release/Simvastatin tablet (500 mg/10 mg).

RESUMEN

In the present study, a simple, rapid, and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of the concentration of Nifekalant in human plasma was developed and validated. The analyte and the internal standard were extracted from human plasma using dichloromethane and analyzed using an ultra-fast liquid chromatographer (UFLC) coupled to an electrospray ionization (ESI) tandem mass spectrometer in the positive mode. The chromatographic analysis was performed isocratically on an Inertsil ODS-SP column (150mm×4.6mm I.D., 5µm). The mobile phase was a mixture of 15% 10mM aqueous ammonium formate and 85% methanol (the pH was adjusted to 3.5 with formic acid) at a flow rate of 0.8mL/min with a split ratio of 1:1 to the ionization source. The lower limit of quantification (LLOQ) was 5.05ng/mL, and a linear calibration curve was obtained over the concentration range of 5.05 to 3030ng/mL. The intra-day and inter-day assay variations were less than 9.06%, and the accuracy values (relative error) were in the range of -10.95% to 2.27%. The essential pharmacokinetic parameters of the intravenously injection of Nifekalant were found to be the following: t1/2=1.26±0.16h,Cmax=1.943±0.411mg/L, and AUC0-12h=4.600±0.756mg/L·h.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Pirimidinonas/sangre , Espectrometría de Masas en Tándem/métodos , Adulto , Estabilidad de Medicamentos , Femenino , Humanos , Límite de Detección , Modelos Lineales , Masculino , Pirimidinonas/química , Pirimidinonas/farmacocinética , Reproducibilidad de los Resultados

RESUMEN

Arotinoid acid (Ro 13-7410) is the third generation of synthetic retinoid, which was developed for the treatment of psoriasis and other hyperkeratotic skin disorders. The therapeutically active dose is less than 0.5microg/kg body weight/day. To investigate the pharmacokinetics of arotinoid acid, a sensitive and selective liquid chromatographic-tandem mass spectrometric method (LC-MS/MS) for the determination of arotinoid acid in human plasma was developed and validated. The sample processing was carried out in the dark to minimize photodegradation of the analytes. Arotinoid acid and the internal standard (IS), acitretin, were extracted from plasma samples using solid phase extraction with Oasis HLB cartridges. Chromatographic separation was achieved on a Zorbax Extend C(18) column (150mmx4.6mm, i.d., 5microm) using methanol:acetonitrile:5mM ammonium acetate (48:32:20, v/v/v) as the mobile phase at a flow rate of 0.8mL/min. The detection was carried out in multiple reaction monitoring (MRM) mode via negative electrospray ionization (ESI) interface. The lower limit of quantification (LLOQ) achieved was 37.1pg/mL with intra-day and inter-day precision (RSD) of 8.7% and 8.5%, and accuracy (RE) of 2.0%. Inter-day and intra-day RSD for three quality control levels (QCs) across validation runs were less than 11.0% and the accuracy ranged from 1.9% to 3.3%. The validated LC-MS/MS method was applied to a phase I clinical pharmacokinetic study after a single oral administration of 40microg arotinoid trometamol to healthy subjects.

Asunto(s)

Benzoatos/sangre , Cromatografía Liquida/métodos , Retinoides/sangre , Espectrometría de Masas en Tándem/métodos , Acitretina/análisis , Benzoatos/farmacocinética , Estabilidad de Medicamentos , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Reproducibilidad de los Resultados , Retinoides/farmacocinética , Sensibilidad y Especificidad , Extracción en Fase Sólida/métodos

RESUMEN

A novel method for the quantitation of yonkenafil, a new synthetic phosphodiesterase V inhibitor, in rat plasma using high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) has been developed. The analyte and internal standard (diazepam) were extracted from plasma (100 microl) by liquid-liquid extraction and separated on a C18 column using 10mM ammonium acetate buffer: methanol (15:85, v/v) as mobile phase in a run time of 3.0 min. The detector was a Q-trap mass spectrometer with an ESI interface operating in the multiple reaction monitoring (MRM) mode. The assay was linear over the concentration range 1.0-1000 ng/ml with a limit of detection of 0.20 ng/ml. Intra- and inter-day precision (as relative standard deviation) were both within 8.45% with good accuracy. The method was successfully applied to a preclinical pharmacokinetic study of yonkenafil in rat after sublingual, oral and intravenous administration. The results demonstrate that the sublingual route gives a higher bioavailablity than the oral route and may represent a useful alternative route of yonkenafil administration.

Asunto(s)

Cromatografía Liquida/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/farmacocinética , Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa/sangre , Inhibidores de Fosfodiesterasa/farmacocinética , Pirimidinonas/sangre , Pirimidinonas/farmacocinética , Pirroles/sangre , Pirroles/farmacocinética , Espectrometría de Masas en Tándem/métodos , Acetatos/química , Administración Oral , Administración Sublingual , Animales , Disponibilidad Biológica , Tampones (Química) , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/administración & dosificación , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Ayuno , Concentración de Iones de Hidrógeno , Inyecciones Intravenosas , Masculino , Metanol/química , Estructura Molecular , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Pirimidinonas/administración & dosificación , Pirimidinonas/química , Pirroles/administración & dosificación , Pirroles/química , Control de Calidad , Distribución Aleatoria , Ratas , Ratas Wistar , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masa por Ionización de Electrospray , Factores de Tiempo

RESUMEN

This paper describes a rapid and sensitive analytical method for the quantitation of iptakalim, a novel antihypertensive drug, in human plasma. The method is based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) using sildenafil as internal standard. Sample preparation involved liquid-liquid extraction with dichloromethane-diethyl ether (2:3, v/v) in a basic environment. Chromatography was carried out on an amino column with a mobile phase consisting of acetonitrile-water (55:45, v/v, water containing 0.5% formic acid). Detection employed electrospray ionization (ESI) tandem mass spectrometry in the multiple-reaction-monitoring (MRM) mode. The assay was linear in the concentration range of 0.5-100 ng/ml with a lower limit of quantitation (LLOQ) of 0.5 ng/ml. Intra- and inter-day precision (R.S.D.) were <4.5% and <12.0%, respectively and the accuracy (R.E.) was in the range +/-5%. The method was successfully applied to a single oral dose pharmacokinetic study in human volunteers.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Propilaminas/sangre , Espectrometría de Masas en Tándem/métodos , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad

RESUMEN

A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated for simultaneous quantification of valsartan and hydrochlorothiazide in human plasma. After a simple protein precipitation using acetonitrile, the analytes were separated on a Zorbax SB-Aq C18 column using acetonitrile-10mM ammonium acetate (60:40, v/v, pH 4.5) as mobile phase at a flow rate of 1.2 mL/min. Valsartan and hydrochlorothiazide were eluted at 2.08 min and 1.50 min, respectively, ionized using ESI source, and then detected by multiple reaction monitoring (MRM) mode. The precursor to product ion transitions of m/z 434.2-350.2 and m/z 295.9-268.9 were used to quantify valsartan and hydrochlorothiazide, respectively. The method was linear in the concentration range of 4-3600 ng/mL for valsartan and 1-900 ng/mL for hydrochlorothiazide. The method was successfully employed in a pharmacokinetic study after an oral administration of a dispersible tablet containing 80 mg valsartan and 12.5 mg hydrochlorothiazide to each of the 20 healthy volunteers.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Hidroclorotiazida/sangre , Espectrometría de Masas en Tándem/métodos , Tetrazoles/sangre , Valina/análogos & derivados , Humanos , Hidroclorotiazida/farmacocinética , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tetrazoles/farmacocinética , Valina/sangre , Valina/farmacocinética , Valsartán

RESUMEN

A rapid and sensitive LC-MS/MS method for quantifying Armillarisin A in human plasma after a single oral dose (40 mg) has been developed and validated. Sample preparation used liquid-liquid extraction with a mixture of diethyl ether-dichloromethane (60:40, v/v) in an acidic environment. The retention times of Armillarisin A and the internal standard, probenecid, were 1.63 and 1.78 min, respectively. The calibration curve was linear over the range 0.15-50 ng/mL with a limit of quantitation of 0.15 ng/mL. The coefficient of variation as a measure of intra- and inter-day precision was <9.3% and the accuracy was in the range 92.5-108.0%. The Armillarisin A concentration-time profile in human plasma was determined after an oral dose of a 40 mg tablet.

Asunto(s)

Benzopiranos/sangre , Cromatografía Liquida/métodos , Cumarinas/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Administración Oral , Benzopiranos/administración & dosificación , Benzopiranos/química , Benzopiranos/farmacocinética , Calibración , Cumarinas/administración & dosificación , Cumarinas/química , Cumarinas/farmacocinética , Éter/química , Humanos , Cloruro de Metileno/química , Estructura Molecular , Probenecid/química , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Comprimidos , Factores de Tiempo

RESUMEN

A rapid, selective and sensitive method for the determination of the angiotensin II receptor antagonist, telmisartan, in human plasma has been developed. Telmisartan and the internal standard, diphenhydramine, were extracted from plasma using diethyl ether-dichloromethane (60:40, v/v), and separated on a Zorbax extend C(18) column using methanol-10mM ammonium acetate (85:15, v/v) adjusted to pH 4.5 after mixing with formic acid as mobile phase. Detection was carried out by multiple reaction monitoring on a Q-trap LC-MS/MS system with an ESI interface. The assay was linear over the range 0.5-600.0 ng/ml with a limit of quantitation of 0.5 ng/ml and a limit of detection of 0.05 ng/ml. Intra- and inter-day precision were <6.7% and <8.1%, respectively, and the accuracy was in the range 88.9-111.0%. The assay was applied to a pharmacokinetic study of telmisartan given as a single oral dose (80 mg) to healthy volunteers.

Asunto(s)

Bencimidazoles/sangre , Benzoatos/sangre , Cromatografía Liquida/métodos , Espectrometría de Masas/métodos , Humanos , Estándares de Referencia , Sensibilidad y Especificidad , Telmisartán

RESUMEN

Dioscin (diosgenyl 2,4-di-O-alpha-l-rhamnopyranosyl-beta-d-glucopyranoside) is an important constituent of some traditional Chinese medicines with several bioactivities. We have investigated the pharmacokinetics of dioscin in rat after intravenous and oral administrations. Compartmental methods were used to perform pharmacokinetic data analysis. The dose-dependent pharmacokinetics of dioscin was characterized after intravenous administrations (0.064, 0.16, 0.4 and 1.0mg/kg) to rats. There was significant decrease in clearance with increasing dose (4.67+/-0.09 ml/min/kg (0.064 mg/kg) versus 3.49+/-0.23 ml/min/kg (1.0 mg/kg), P<0.05), and the plot of reciprocal clearance values versus the doses was linear (r=0.909, P<0.05). After an I.V. dose of 1mg/kg, simultaneous oral gavage of activated charcoal did not change the pharmacokinetic parameters indicating enterohepatic recycling of dioscin is not important in rat. The absolute oral bioavailability was very low (0.2%). In tissue distribution and bile excretion studies after I.V. and oral administrations, dioscin was shown to undergo a prolonged absorption from the intestinal tract and slow elimination from organs, and only a small amount of drug was recovered in bile. The cumulative amounts of dioscin in feces and urine indicated that the parent drug is mainly excreted in the feces.

Asunto(s)

Diosgenina/análogos & derivados , Administración Oral , Animales , Bilis/metabolismo , Disponibilidad Biológica , Biotransformación , Diosgenina/administración & dosificación , Diosgenina/química , Diosgenina/metabolismo , Diosgenina/farmacocinética , Diosgenina/farmacología , Diosgenina/orina , Relación Dosis-Respuesta a Droga , Heces/química , Femenino , Inyecciones Intravenosas , Masculino , Estructura Molecular , Ratas , Ratas Wistar , Distribución Tisular , Orina/química

RESUMEN

A rapid and sensitive LC-MS-MS method for quantifying levodropropizine in human plasma after oral administration of a single-dose (60 mg/day) was developed and validated. The sample preparation used liquid-liquid extraction with a mixture of dichloromethane-diethyl ether (2:3, v/v) in a basic environment. The retention time of levodropropizne and zolmitriptan (used as internal standard) was 1.6 and 1.4 min, respectively. The assay was linear over the range 0.25-500 ng/mL with a LOQ of 0.25 ng/mL. The intra- and inter-day precision were < 8.1% and < 11.5%, respectively, and the accuracy was in the range 87.6-112%. The levodropropizine concentration profile in human plasma was determined.

Asunto(s)

Antitusígenos/sangre , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas/métodos , Glicoles de Propileno/sangre , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad

RESUMEN

A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS-MS) method for the determination of metformin in human plasma using phenformin as internal standard has been developed and validated. Sample preparation of plasma involved acidification with acetic acid, deproteination with acetonitrile and washing with dichloromethane. Samples were then analyzed by HPLC on a short Nucleosil C18 column (5 microm, 50 mm x 4.6 mm i.d.) using a mobile phase consisting of acetonitrile:methanol:10mM ammonium acetate pH 7.0 (20:20:60, v/v/v) delivered at 0.65 ml/min. Detection was performed using an Applied Biosystems Sciex API 4000 mass spectrometer set at unit resolution in the multiple reaction monitoring (MRM) mode. Atmospheric pressure chemical ionization (APCI) was used for ion production. The assay was linear over the range 1-2000 ng/ml with intra- and inter-day precision of <8.6% and accuracy in the range 91-110%. The limit of detection was 250 pg/ml in plasma. The method was successfully applied to a clinical pharmacokinetic study of an extended-release tablet of metformin hydrochloride (500 mg) administered as a single oral dose.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Hipoglucemiantes/sangre , Espectrometría de Masas/métodos , Metformina/sangre , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad