Comparison of liquid chromatography-ultraviolet and chromatography-tandem mass spectrometry for the determination of indapamide in human whole blood and their applications in bioequivalence studies.

The aim of this study was to compare two methods which were based on liquid chromatography with ultraviolet detection (LC-UV) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively, to determine indapamide (CAS 26807-65-8) and to apply them to bioequivalence studies. The universal parameters, including selectivity, linearity, precision, and quantification limit, served as gold standard for the comparison of the two methods. As a result, the two methods were both very consistent and reliable. Furthermore, the LC-MS/MS method required only one-fifth the blood volume needed by the other method and was approximately 25 times more sensitive than the other method. The total run time of the LC-MS/MS method was 3.5 min per sample as opposed to 11 min for the other method. Forty healthy male Chinese volunteers were selected as subjects. One half were orally administrered 2.5 mg indapamide immediate release tablets while the other half were orally administered 1.5 mg indapamide sus-tained release coated tablets. The collected blood samples were determined with the two methods described above. The pharmacokinetic parameters were determined using a noncompartmental method. For the bioequivalence studies, the pharmacokinetic parameters acquired here were in line with the literature and parameters met the criteria set by the State Food and Drug Administration of China (SFDA) for bioequivalence study, indicating that generic drugs are bioequivalent to branded drugs. The present study suggests that the two methods based on LC-UV and LC-MS/MS were suitable for bioavailability studies of indapamide with different pharmaceutical formulations. Consequently, it can be believed that the criterion that each individual expected concentration range would need a given bioassay with the requested sensitivity is not absolutely right. In practice, most of the time, the highest sensitivity allows to bioassay concentrations in a higher range.

Safety, tolerability and pharmacokinetics of phenoprolamine hydrochloride floating sustained-release tablets in healthy Chinese subjects.

The present study was designed to assess the safety, tolerability and pharmacokinetics of phenoprolamine hydrochloride floating sustained tablets (PHFST) in healthy Chinese subjects. 116 volunteers were randomized into single- or multiple-dose groups for oral administration 30-240 mg of PHFST once or 60-120 mg twice daily. Safety and tolerability were appraised by monitoring adverse events and laboratory parameters. Pharmacokinetics was assessed by determining the plasma concentrations of phenoprolamine hydrochloride with a validated HPLC method. In single-dose studies, no severe adverse events were observed in volunteers, and all adverse events were mild; the percentages of treatment-emergent events judged to be possibly related to the drug were 3/6 in the 240 mg dose group, 1/6 in the 180-210 mg dose groups, and none in the 30-150 mg dose groups; system exposure (AUC, C(max)) increased with respect to dose at 30-120 mg, whereas AUC raised disproportionately with dose escalating from 120 to 240 mg; the absorption of phenoprolamine hydrochloride was unaffected by food. In multiple studies, no safety concerns were revealed up to 7 days; steady-state plasma concentration was achieved after approximately 4-5 days of repeated twice-daily dosing. PHFST is safe and well tolerated in healthy Chinese subjects. The mean C(max) of PHFST is proportional to dose, but not the AUC. Oral dosing regimen selected for subsequent Phase II/III clinical trials was 60 mg of PHFST, b.i.d., and dose up to 120 mg, b.i.d. - may be used to achieve better antihypertensive effect.

A simple and sensitive HPLC method for quantitation of low phenoprolamine hydrochloride concentrations in human plasma and its pharmacokinetic application.

Phenoprolamine hydrochloride is a novel compound that works against a variety of types of hypertension. The purpose of this study was to develop a simple and sensitive high-performance liquid chromatographic method for quantitation of low phenoprolamine hydrochloride concentrations in human plasma and to apply it to pharmacokinetic study. The procedure involved extraction of the drug and clonidine (internal standard) from the plasma using diethyl ether. Chromatographic separations were carried out on a 4.6 x 200 mm Hypersil silica column with UV detection at 230 nm. The isocratic mobile phase, 1% ammonium acetate (pH 5.4) and methanol (0.3:99.7, v/v), was run at 1 mL/min. Extraction recovery was 84% for phenoprolamine hydrochloride at a concentration level of 200 ng/mL, and 76% for clonidine at 200 ng/mL. The method was linear in the concentration range 5-4000 ng/mL with a lower limit of quantitation of 5 ng/mL for phenoprolamine hydrochloride. Inter- and intra-day coefficients of variation were less than 10%. The validated method was successfully applied to a pharmacokinetic study in human after an oral administration of the drug, and the pharmacokinetic parameters are presented.

[Determination of aceclofenac in human plasma by reversed-phase high performance liquid chromatography].

A simple and rapid reversed-phase high performance liquid chromatographic (RP-HPLC) method for the determination of aceclofenac in human plasma has been established. Plasma samples from 18 male volunteers were collected. The samples were extracted with ether, and the extractant was redissolved in the mobile phase after dried by N2 at 37 degrees C. Chromatography was performed on an ODS column with methanol-0.1 mol/L ammonium acetate (pH 6.0) (7:3, v/v) as the mobile phase. The flow rate was 1.0 mL/min. The UV-Vis detector was set at 275 nm. The linear range was from 0.05 mg/L to 40.0 mg/L with a correlation coefficient of 0.9999. The intra-day and inter-day relative standard deviations (RSDs) for assaying the plasma samples containing three levels of aceclofenac were 1.84%-7.13% and 3.40%-9.33% (n = 5), respectively. The mean absolute recovery was 82.5% and the mean relative recovery was 100.3%. This sensitive and selective method can be used for clinical pharmacokinetic study of aceclofenac.

Pharmacokinetic-pharmacodynamic modeling of daurisoline and dauricine in beagle dogs.

AIM: To study the combined pharmacokinetic-pharmacodynamic (PK-PD) model of daurisoline and dauricine, and compare their effects on cardiac electrophsiology, blood pressure, and hemodynamics in beagle dogs. METHODS: The plasma drug concentration was determined by the reversed-phase HPLC method and the effects on cardiac and hemodynamics were recorded by polygraph. The pharmacokinetic and PK-PD model parameters were calculated. RESULTS: The pharmacokinetics were best fitted to a two-compartment open model, and the relationship between effect and effect compartment concentration of both drugs could be represented by the sigmoid-E(max) model. There were no significant differences in main pharmacokinetics and PK-PD parameters between the two drugs. CONCLUSION: No statistically different kinetic disposition characteristics and potencies of inhibitory effects on myocardial function of daurisoline and dauricine were found in beagle dogs.

[Determination of daurisoline in rabbit plasma and study on its pharmacokinetics].

AIM: To establish an HPLC method for the determination of daurisoline (DS) in rabbit plasma and investigate its pharmacokinetic characteristics after intravenous administration. METHODS: Dauricine was used as internal standard. The plasma samples were deproteinated with acetonitrile and extracted with two-step dichloromethane. Acetonitrile-water-triethylamine (18:82:0.28, pH 3) was used as mobile phase at a flow rate of 1.0 mL.min-1. The UV-detector was set at 284 nm. RESULTS: The linear range was 0.05-20.00 micrograms.h.mL-1 with correlation coefficients 0.9996. The limit of quantitation (LOQ) was 0.05 mg.L-1 of plasma. The absolute and relative recoveries were above 80% and (101 +/- 5)%, respectively. The intra- and inter-assay coefficient of variation were 1.9%-5.6% and 3.5%-6.5%, respectively. The plasma concentration-time profiles were adequately described by a two-compartment open model. CONCLUSION: A sensitive, precise and accurate method for the determination of DS in plasma was described, which can be used in its pharmacokinetic studies.

Study on the pharmacokinetics and relative bioavailability of irbesartan capsules in healthy volunteers.

The pharmacokinetics and relative bioavailability were studied in 18 healthy volunteers. A single oral dose of 150 mg irbesartan capsule (test) or tablet (reference) was given to each volunteer according to a randomized 2-way crossover study. The concentrations in plasma were determined by HPLC-UV method. The main parameters of irbesartan capsules were: Cmax: 1.502 +/- 0.295 micrograms/ml, tmax: 1.44 +/- 0.34 h, t 1/2: 20.21 +/- 14.71 h, AUC0-t: 11.087 +/- 3.443 micrograms/ml-1.h. The relative bioavailability of capsule to tablet was (101.4 +/- 28.9)%. The results of statistical analysis showed that two formulations were bioequivalent.