Determinations of mifepristone and its metabolites and their pharmacokinetics in healthy female Chinese subjects.

The aim of this study is to establish an HPLC method for simultaneous determinations of mifepristone and its metabolites, mono-demethylated mifepristone, di-demethylated mifepristone and C-hydroxylated mifepristone in plasma and to evaluate the pharmacokinetic characteristics of mifepristone tablet. Twenty healthy female Chinese subjects were recruited and a series of blood samples were collected before and after 0.25, 0.5, 1.0, 1.5, 2.0, 4.0, 8.0, 12.0, 24.0, 48.0, 72.0 and 96.0 hours administration by a single oral dose of 75 mg mifepristone tablet. Mifepristone and its three metabolites were extracted from plasma using ethyl acetate and determined by high performance liquid chromatography. The main pharmacokinetic parameters of mifepristone and its metabolites, including Cmax, tmax, MRT, t(1/2), V, CL, AUC(0-96 h) and AUC(0-infinity), were calculated by Drug and Statistical Software Version 2.0. The simple, accurate and stable method allows the sensitive determinations of mifepristone and its metabolites in human plasma up to 4 days after oral administration of 75 mg mifepristone tablet and the clinical applications of their pharmacokinetic studies.

Bioequivalence of nifedipine softgel and capsule in healthy Chinese volunteers by liquid chromatography-mass spectrometry.

The study aimed to compare and evaluate the bioequivalence of Calcigard-10 softgel and Adalat 10 capsule in healthy Chinese volunteers in a randomized, two-way cross over study design with a washout period of 7 days. A sensitive and reproducible electro-spray ionization liquid chromatography-mass spectrometry (ESI-LCMS) assay was developed and validated to determine nifedipine in human plasma using nitrendipine as internal standard. Nifedipine and nitrendipine were extracted from plasma using liquid-liquid extraction with methylene chloride as extraction solvent. The separation was performed by a Diamonsil ODS column (150 x 4.6 mm, 5 microm). The mobile phase was consisted of acetonitrile-5 mM ammonium acetate (52:48, v/v), delivered at flow rate of 1 mL/min. The 90% confidence intervals for the ratio values of logarithmic transformed Cmax and AUC were calculated to evaluate the bioequivalence of two preparations. The values of Cmax (92.3-112.7%), AUC0-t (84.5-95.1%) and AUC0-inf (84.4-95.5%) are within the interval criterion of 70-143% for Cmax and 80-125% for AUC. The Calcigard-10 softgel and Adalat 10 capsule are bioequivalent.

Comparison of different pharmacodynamic models for pharmacokinetic-pharmacodynamic (PK-PD) modeling of carvedilol.

The paper is aimed to investigate the pharmacokinetic (PK) and the pharmacodynamic (PD) properties of carvedilol using indirect response and effect-compartment link models, and compare the fitness of PK-PD models. Twenty male healthy Chinese volunteers received a single oral dose of 20 mg of carvedilol. The plasma concentrations of carvedilol were determined by reversed-phase HPLC method with fluorescence detection, and the pharmacokinetic parameters were calculated by DAS2.0. The mean arterial blood pressure was measured and the pharmacodynamics of carvedilol was characterized by tail-cuff manometry. The main pharmacokinetic parameters of carvedilol were as follows, t1/2 (4.56 +/- 2.56) h, Cmax (46.29 +/- 21.07) ng x mL(-1), AUC(0-infinity) (173.76 +/- 87.36) ng x mL(-1) x h. The estimated Kin was (0.41 +/- 0.31)% h(-1), Kout was (0.40 +/- 0.26) h(-1), the IC50 value was (24.40 +/- 21.10) ng x mL(-1) and the area under the effect curve (AUE) was (3.82 +/- 1.46)% h for the indirect response PD model. The Ke0 was (0.35 +/- 0.27) h(-1), the EC50 was (24.30 +/- 24.30) ng x mL(-1), and the AUE was (5.65 +/- 2.54)% h for the effect-compartment model. The HPLC method can be used for the pharmacokinetic study of carvedilol. The proposed effect-compartment link model provided more appropriate and better-fitting PK/PD characteristics than the indirect response model in Chinese healthy volunteers according to Akaike's information criterion values.

Determination of bergenin in human plasma after oral administration by HPLC-MS/MS method and its pharmacokinetic study.

A highly sensitive, simple and selective high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and applied to the determination of bergenin concentration in human plasma. Bergenin and the internal standard (IS) thiamphenicol in plasma were extracted with ethyl acetate, separated on a C(18 )reversed-phase column, eluted with mobile phase of acetonitrile-water, ionized by negative ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor --> product ions of m/z 327.1 --> 192 for bergenin and 354 --> 185.1 for the IS, respectively. The linear range of the calibration curve for bergenin was 0.25-60 ng mL(-1), with the lowest limit of quantification of 0.25 ng mL(-1), and the intra/inter-day relative standard deviation (RSD) was less than 10%. The method is suitable for the determination of low bergenin concentration in human plasma after therapeutic oral doses, and has been first and successfully used for its pharmacokinetic studies in healthy Chinese volunteers.

[HPLC-MS/MS method for determination of sodium cromoglycate concentration in human plasma and its pharmacokinetics].

The study established an HPLC-MS/MS method for determining the concentrations of sodium cromoglycate in human plasma and evaluated the pharmacokinetics of nasal drops and nasal spray. A C18 column was used to separate sodium cromoglycate in plasma with a mobile phase of a mixture of ammonium-methanol (involves 50% acetonitrile) (15:85) at a flow rate of 0.4 mL x min(-1). Electronic spray ionization (ESI) and multiple-reaction monitoring (MRM) were used for the determination of sodium cromoglycate in human plasma. The linear range of the standard curve of sodium cromoglycate was from 0.3 to 20 ng x mL(-1), and the minimum concentration of detection was 0.3 ng x mL(-1). The extraction recovery was more than 94.1%, intra-day and inter-day RSD were less than 14.3%. After a single dose of sodium cromoglycate, the main pharmacokinetic parameters of nasal spray and nasal drops were as follows, T(1/2)(1.82 +/- 0.54) h, (1.59 +/- 0.52) h; Tmax (0.47 +/- 0.12) h, (0.44 +/- 0.15) h; Cmax, (9.79 +/- 4.66) ng x mL(-1), (10.88 +/- 4.05) ng x mL(-1); AUC(0-5 h)(11.52 +/- 3.46) ng x mL(-1) x h x h, (12.63 +/- 4.23) ng x mL(-1) x h, Fr(93.6 +/- 13.8)%. The method is sensitive, rapid and accurate. It is suitable for therapeutic drug monitoring and human pharmacokinetic study of sodium cromoglycate.

Determination of betamethasone in human plasma by liquid chromatography with tandem mass.

A sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of betamethasone in human plasma. The analyte was isocratically eluted on a Venusil XBP C8 column (200 mm x 3.9 mm ID, 5 microm) with methanol-water mol x L(-1) ammonium formate) (80:20) at a flow rate of 0.4 mL x min(-1), and detected (containing 5 mmol x L(-1) ammonium formate) (80:20) at a flow rate of 0.4 mL x min(-1), and detected with a triple quad LC-MS/MS using ESI with positive ionization. Ions monitored in the multiple reaction monitoring (MRM) mode were m/z 393.3-->355.2 for betamethasone and m/z 361.3-->343.2 for prednisolone (IS). Betamethasone was extracted from 0.5 mL human plasma with ethyl acetate. The average recovery is 88.24% and the low limit of quantitation (LLOQ) was 0.5 ng x mL(-1). The 3-day validation study demonstrated excellent precision and accuracy across the calibration range of 0.5-80.0 ng x mL(-1). The method was successfully applied to the pharmacokinetic study of compound betamethason injection in healthy Chinese volunteers.

Determination of sodium cromoglycate in human plasma by liquid chromatography with tandem mass.

A sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of sodium cromoglycate (SCG) in human plasma after a nasal dose of 10.4 mg sodium cromoglycate nasal spray, using pravastatin sodium as the internal standard. The method was validated over a linear range of 0.300-20.0 ng/mL. SCG and I.S. were extracted from 1.0 mL of heparinized plasma by C(18) solid-phase extraction cartridges using methanol as eluting solvent. The dried residue was reconstituted with 100 microL of mobile phase, and 10 microL was injected onto the LC-MS/MS system. Chromatographic separation was achieved on a C(18) column (250 x 4.6 mm i.d., 5 microm particle size) with a mobile phase of methanol-acetonitrile-water (containing 2 mmol/L ammonium acetate; 42.5:42.5:15, v/v/v) at a flow rate of 0.4 mL/min. The analytes were detected with a triple quad LC-MS/MS using ESI with positive ionization. Ions monitored in the multiple reaction monitoring mode were m/z 469.0 (precursor ion) to m/z 245.0 (product ion) for SCG and m/z 447.2 (precursor ion) to m/z327.1 (product ion) for pravastatin sodium (internal standard) The average recovery of SCG from human plasma was 94.88% and the lower limit of quantitation was 0.3 ng/mL. Results from a 3-day validation study demonstrated excellent precision and accuracy across the calibration range of 0.3-20 ng/mL. The method was successfully applied to the pharmacokinetic study of SCG in healthy Chinese volunteers.

Determination and pharmacokinetic study of norcantharidin in human serum by HPLC-MS/MS method.

A sensitive, simple and selective high-performance liquid chromatography-tandem mass spectrometry method was developed and applied to the determination of norcantharidin concentration in human serum. Norcantharidin (NCTD) and cyclophosphamide (IS) in serum were extracted with acetone, separated on a C18 reversed-phase column, gradiently eluted with a mobile phase of acetonitrile-water containing 2 mm ammonium acetate and 0.1% formic acid (pH 3), ionized by positive ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor-->product ions of m/z 169.3-->123.1 for NCTD and 261.2-->140.2 for IS, respectively. The linear range of the calibration curve for NCTD was 2.5-50 ng/mL, with a lowest limit of quantification of 2.5 ng/mL, and the intra/inter-day RSD was less than 10%. The method was suitable for determination of low NCTD concentration in human serum after therapeutic oral doses, and has been successfully used for pharmacokinetic studies in healthy Chinese volunteers.