AUC 0-infinity Research Articles

200. Clinical trial of metformin to treat preterm preeclampsia: pharmacokinetics and biomarker studies

Introduction Metformin is a potential therapeutic for preeclampsia as it decreases sFlt-1 and soluble endoglin and rescues endothelial dysfunction. Metformin pharmacokinetics in preeclampsia, where there is increased renal clearance and proteinuria, has not been established. Objective/Hypothesis To evaluate metformin XR (extended release) pharmacokinetics in preterm preeclampsia, obtain data on pregnancy prolongation and circulating levels of biomarkers associated with endothelial dysfunction. Methods 15 women with preterm preeclampsia were treated with 1.5 g metformin XR twice daily. Pharmacokinetic sampling was performed on day 1 at 2,4,5,6,7,8,24 h, and concentrations measured using liquid chromatography-tandem mass spectrometry. Given steady state is reached at 24–48 h, trough concentrations were measured at day 1 and 5 to assess the increase in Cmin over time. Plasma was taken twice weekly and biomarkers of endothelial dysfunction measured. Results Gestation at recruitment ranged from 27 to 31 weeks, and median prolongation was 11.5 days [IQR 5.8–23.8]. Pharmacokinetic studies confirmed excellent circulating levels at 0–12 h exposure, with Cmax [median (IQR)] 1.6 (1.3–1.9) mg/l, AUC 0–12 11.7 (8.9–13.5) mg.h/l and AUC 0-infinity 17.0 (10.7–36.6) mg.h/l. Day 1 and 5 trough concentrations were 0.55 (0.34–1.22) mg/l and 0.01 (0.01–0.70) mg/l suggesting steady state exposure is similar to day 1. Umbilical cord blood:plasma ratios taken 4 (3–9.5) hours after dosing were 0.67 (0.2–0.86). None of the following circulating biomarkers increased across pregnancy among those who remain undelivered: sFlt1, soluble endoglin, Vascular Cell Adhesion Molecule 1, Endothelin-1 and placental growth factor. Discussion 1.5 g of metformin XL twice daily in preterm preeclampsia resulted in at least the same exposure as 2 g daily in healthy controls, despite pregnancy and preeclampsia related changes. Metformin potentially stabilised levels of circulating biomarkers of endothelial dysfunction. Randomised trials to treat preterm preeclampsia should be performed.

Pharmacokinetics and bioavailability study of neoline in Beagle dogs

This paper is aim to investigate the pharmacokinetics and absolute bioavailability of neoline in Beagle dogs, and provide a theoretical basis for further study. Ethyl acetate was used for liquid-liquid extracting after 10% ammonia alkalizing. The method of UPLC-Q-TOF-MS was established for the determination of neoline plasma concentrations. Beagle dogs were orally or intravenously administered with neoline for pharmacokinetic and absolute bioavailability study. Good linear relationship of neoline was found over the range of 0.1-4 mg x L(-1) (R2 = 0.9982) and 2-100 microg x L(-1) (R2 = 0.9945). Intra-and inter-day precision, expressed as the relativestandard (RSD) were less than 5.0%. Accuracy, expressed as the relative error (RE) was within 90.0%-115%. The recovery of neoline in dog plasma was more than 80%. After 6 mg x kg(-1) for ig and 1 mg x kg(-1) for iv administration of neoline, the main pharmacokinetic parameters were analyzed with Winnonlin software. t(1/2) were (313.88 +/- 63.18), (236.33 +/- 229.84) min, and AUC(0-infinity) were (58,027.40 +/- 14,132.69), (473,578.02 +/- 82,333.08) min x microg x L(-1) for ig and iv administration respectively. The absolute bioavail ability was (73.15 +/- 10.29) %. The method of UPLC-Q-TOF-MS described in the report was sensitive, reliable and specific, and suitable for pharmacokinetic study of neoline in Beagle dog. The high absolute bioavailability of neoline in dog suggested good absorption of neline which was worth of further investigation.

Pharmacokinetic study after single oral dose of beta-lactam and fluoroquinolone antimicrobials in Bangladeshi healthy male volunteers

The variability of response to antimicrobial has been inadequately explained because of lack of pharmacokinetic data. The present pharmacokinetic study was designed to provide information beneficial to formulate a population pharmacokinetic model appropriate for Bangladeshi population. Among the beta-lactams, amoxicillin (500 mg), flucloxacillin (250 mg), cefuroxime (500 mg) and among the fluoroquinolones, ciprofloxacin (500 mg), levofloxacin (500 mg), gatifloxacin (400 mg) were studied in 15 healthy Bangladeshi male volunteers. The Cmax, AUC0–infinity, Tmax, T1/2 and Ctrough were studied with all antimicrobials. Later, the Cmax and AUC0–infinity were adjusted for bodyweight and dose. Among the studied antimicrobials, the Cmax varied to great extent even after adjustment for bodyweight and dose. The Cmax after adjustment was highest in case of flucloxacillin and lowest in case of ciprofloxacin, indicating excellent absorption of flucloxacillin in Bangladeshi population. The information obtained through this study generates necessity of new cut-off value for the antimicrobials.DOI: http://dx.doi.org/10.3329/bjpp.v30i1.20789 Bangladesh J Physiol Pharmacol 2014; 30(1):16-24

Studies on effects of Achyranthes bidentata on Tongsaimai pellets main active ingredients chlorogenic acid, isoliquiritin, harpagoside and glycyrrhizin in vivo pharmacokinetics

To study on the effects of Achyranthes bidentata on Tongsaimai pellets main active ingredients chlorogenic acid, isoliquiritin, harpagoside and glycyrrhizin in rats in vivo pharmacokinetic behaviors, a method for the simultaneous determination of chlorogenic acid, isoliquiritin, harpagoside and liquiritigenin in rat plasma was established by UPLC-MS/MS. The analysis was performed on a waters Acquity BEH C18 column (2.1 mm x 100 mm, 1.7 microm) with the mixture of acetonitrile and 0.1% formic acid/water as mobile phase, and the gradient elution at a flow rate of 0.3 mL x min(-1). The analytes were detected by tandem mass spectrometry with the electrospray ionization (ESI) source and in the multiple reaction monitoring (MRM) mode. It turned out that the analytes of Tongsaimai pellets groups C(max) and AUC(Q-infinity) values were higher than that with A. bidentata group, and the C(max) values of chlorogenic acid had significantly difference (P < 0.05), the AUC(0-infinity) values of chlorogenic acid and glycyrrhizin had significantly difference (P < 0.05); The T(max) and CL values of two groups had no significantly difference. Results showed that the established method was specific, rapid, accurate and sensitive for the studies of Tongsaimai pellets four main active ingredients in rat in vivo pharmacokinetic, and A. bidentata have varying degrees of effects on Tongsaimai pellets four main active ingredients in rat in vivo pharmacokinetic behaviors.

Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose

To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD < 15%). The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC.

Determination of morroniside concentration in beagle plasma and its pharmacokinetics by high performance liquid chromatography-tandem mass spectrometry

A sensitive, simple and specific high performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) method was developed for the determination of morroniside in the plasma of beagles administered via intragastric (ig) doses of morroniside. The method employed paeoniflorin as the internal standard and extracted by simple protein precipitation. The separation was achieved using an Inertsil ODS-SP column (50 mm x 2.1 mm, 5 microm) with mobile phases of 1 mmol/L sodium formate aqueous solution and acetonitrile (gradient elution) at a flow rate of 0.4 mL/min. The detection was accomplished by a mass spectrometer using multiple reaction monitoring (MRM) in positive mode. Pharmacokinetic parameters were fitted by software DAS 2.0. The methodological study showed a good linear relationship of 2-5 000 microg/L (r = 0.996 6) with a sensitivity of 2 microg/L as the limit of quantification. The precision, accuracy, mean recoveries and the matrix effects were satisfied with the requirements of biological sample measurement. The method described above was successfully applied to the pharmacokinetic study of morroniside in the beagle plasma samples. The area under the plasma concentration-time curves (AUC(0-infinity)) of morroniside after single ig administration doses of 5, 15 and 45 mg/kg were (1 631.20 +/- 238.50), (3 984.05 +/- 750.38) and (10 397.64 +/- 3 156.34) microg/L x h. The relationship between dose and AUC showed a good linearity. The pharmacokinetic property of morroniside was proposed to be linear pharmacokinetics.

Determination of ilaprazole in beagle plasma and its pharmacokinetics by high performance liquid chromatography-mass spectrometry

A sensitive, simple and specific high performance liquid chromatography-electro spray ionization mass spectrometry method was developed for the determination of ilaprazole in the plasma of beagles administered via i.v. bolus doses of ilaprazole. The procedure employed buspirone as the internal standard and a simple protein precipitation step. The separation was achieved using a C18 column (100 mm x 2.1 mm, 5 microm) with a mobile phase consisting of water-methanol-acetonitrile (69:8:23, v/v/v) containing 0.1% (v/v) formic acid at a flow rate of 0.2 mL/min. The detection was accomplished by a mass spectrometer using selected ion monitoring (SIM) in positive mode. The linearity was from 5 microg/L to 10,000 microg/L with a sensitivity of 5 microg/L as the lower limit of quantification. The inter- and intra- day precisions were within 9.00%. The mean recoveries at three spiked levels were about 106% and the matrix effects were less than 142.0%. The method described above was successfully applied to analyze the beagle plasma samples of ilaprazole in a pharmacokinetic study. The area under the plasma concentration-time curve (AUC(0-infinity) of ilaprazole after i.v. doses of 0.2, 0.8 and 3.2 mg/kg were (2.4 x 10(4) +/- 3 x 10(3)), (8.8 x 10(4) +/- 1.6 x 10(4)) and (5.4 x 10(5) +/- 8 x 10(4)) microg/L x min, respectively. On the basis of AUC, the pharmacokinetic property of ilaprazole was proposed to be linear dynamics.

Surface Stabilized Efavirenz Nanoparticles for Oral Bioavailability Enhancement

The aim of the present study was to prepare surface stabilized nanoparticles for oral bioavailability enhancement of efavirenz (EFZ). EFZ nanoparticles (EFZ-NPs) were prepared by combination of anti-solvent precipitation and high pressure homogenization technique, using hydroxy propyl methyl cellulose as stabilizer which resulted in formation of EFZ-NPs of average particle size -350 nm with excellent particles size distribution (< 0.2). EFZ-NPs were freeze dried using trehalose as cryoprotectant and found to be quite stable against storage at 25 +/- 2 degrees C/60 +/- 5% RH and 40 +/- 2 degrees C/75 +/- 5% RH as evidenced from particle size, particle size distribution and drug content. EFZ-NPs demonstrated an increase in saturation solubility by 5.16 folds in comparison with free EFZ. In vitro dissolution studies established advantage of EFZ-NPs over free EFZ as more than 75% drug was dissolved within 5 min in case of EFZ-NPs while it was approx 20% in case of free EFZ. In vivo pharmacokinetic studies further confirmed the potential of EFZ-NPs as 2.02 folds increase in peak plasma concentration and 2.29 folds increase in AUC(0-infinity) were observed in comparison to free EFZ. The In vitro-In vivo relationship of the formulations further suggested higher correlation coefficient of 0.9995 for EFZ-NPs in Levys plot as compared to 0.8726 for free EFZ.

A Comparison of Duloxetine Plasma Levels in Postbariatric Surgery Patients Versus Matched Nonsurgical Control Subjects

Bariatric surgery such as the Roux-en-Y gastric bypass (RYGB) is currently used as a treatment for severe obesity. Alteration of the gastrointestinal tract by this procedure suggests a potential for clinically significant alterations in the bioavailability of ingested medications including antidepressants. The purpose of this trial was to determine to what extent the RYGB procedure alters the area under the plasma concentration/time curve (AUC(0-infinity)) of the antidepressant, duloxetine. Ten subjects who were 1 year post-RYGB where compared with healthy control subjects matched for body mass index, age, and sex. Ultrarapid or poor metabolizers for cytochrome P450 2D6 were excluded from the study. Subjects received a single dose of 60 mg of duloxetine. Nineteen plasma samples were obtained during 72 hours to characterize the plasma level profile. The mean AUC(0-infinity) was significantly smaller for the postbariatric surgery (PBS) group (646.74 ng × h/mL [SD, 79.70; range, 539.57-791.62], P = 0.017) compared to the nonsurgical control group (1119.91 ng × h/mL [SD, 593.40; range, 415.5-2426.56]). The Tmax was also significantly shorter for the PBS group (2.2 hours) compared to the nonsurgical control group (6 hours; P = 0.005). No significant difference in Cmax or half-life was identified. To our knowledge, this is the first reported study exploring duloxetine pharmacokinetics PBS. This trial found that the bariatric surgery group was exposed to only 57.7% of duloxetine as compared to the nonsurgery group. This finding suggests that clinicians need to monitor patients closely after bariatric surgery and that further exploration of the effects of bariatric surgery on antidepressant pharmacokinetic parameters is warranted.

Determination of theacrine in rat plasma by RP-HPLC

To establish a method for the determination of theacrine in rat plasma after ig. administration of theacrine. Blood sample was taken timely from the eyes canthus of rats. Plasma was isolated and the protein was precipitated by ethyl acetate. Then the plasma concentration of theacrine was determined with RP-HPLC. Caffeine was used as the internal standard. The chromatographic conditions were as follows: Phenomenex Luna C18 (4.6 mm x 250 mm, 5 microm) at 25 degrees C, a mixture of methanol-water (25: 75) as the mobile phase, at the flow rate of 1.0 mL x min(-1) and the detection wavelength of 290 nm. The linear range of theacrine was 0.5-100 mg x L(-1) (R2 = 0.998 9). The lower limit of quantification was 0.5 mg x L(-1). The intra-day RSD was 1.49% 4.40% and inter-day RSD was 0.80% -10.27%. The average extraction recoveries of theacrine were 90.3% -95.8% at concentrations of 0.5, 5.0, 50 mg x L(-1). The main pharmacokinetic parameters after ig. administration of theacrine at concentration of 30 mg x kg(-1) were as follow: C(max) (35.45 +/- 30 2.68) mg x L(-1), t(max) (0.51 +/- 0.13) h, t1/2 (3.13 +/- 1.37) h, AUC(0-infinity) (2.65.39 +/- 94.71) mg x L(-1) x h. The method has been confirmed to be simple, stable, reproducible and with high specificity, and can be used for the pharmacokinetic study of theacrine in rats.

Convolution and validation of in vitro–in vivo correlation of water-insoluble sustained-release drug (domperidone) by first-order pharmacokinetic one-compartmental model fitting equation

The experimental study presents a brief and comprehensive perspective on the methods of developing a Level A in vitro-in vivo correlation (IVIVC) for extended oral dosage forms of water-insoluble drug domperidone. The study also evaluates the validity and predictability of in vitro-in vivo correlation using the convolution technique by one-compartmental first-order kinetic equation. The IVIVC can be substituted as a surrogate for in vivo bioavailability study for the documentation of bioequivalence studies as mandatory from any regulatory authorities. The in vitro drug release studies for different formulations (fast, moderate, slow) were conducted in different dissolution mediums. The f (2) metric (similarity factor) was used to analyze the dissolution data for determination of the most discriminating dissolution method. The in vivo pharmacokinetics parameters of all the formulations were determined by using liquid chromatography mass spectrometry (LC/MS) methods. The absorption rate constant and percentage of absorption of drugs at different time intervals were calculated by using data convolution. In vitro drug release and in vivo absorption correlation were found to be a linear correlation model, which was developed by using percent absorbed drug release versus percent drug dissolved from the three formulations. Internal and external validation was performed to validate the IVIVC. Predicted domperidone concentrations were obtained by convolution technique using first-order one-compartmental fitting equation. Prediction errors estimated for C (max) and AUC (0-infinity) were found to be within the limit.

Prevalence and antimicrobial susceptibility of anaerobes from patients with periodontal abscess in China

We assessed the safety and pharmacokinetics of arbekacin sulfate (ABK, brand name: Habekacin injection) in single and 7-day multiple administration of ABK 400 and 600 mg as potency to healthy male volunteers. In the single administration of ABK 400 and 600 mg (over 30 min, drip infusion), C(max) values were 41.0 +/- 3.6 microg/mL and 63.0 +/- 9.9 microg/mL, respectively. Serum ABK concentrations at 60 min (C(peak)) after the start of administration were 23.2 +/- 2.9 microg/mL and 38.5 +/- 3.3 microg/mL, respectively, and the mean serum ABK concentrations at 24 hr (C(trough)) after the start of administration were less than 0.4 microg/mL (LOQ: limited of quantitation). C(max), Cpeak and AUC(0-infinity) were increased with doses, and t1/2, CL(tot), CL(r) V(ss) and urinary excretion were comparable at both doses. In the multiple administration of ABK 400 and 600 mg (over 30 min, drip infusion) once a day for 7 days, C(max0, C(peak) and AUC(0-infinity) were comparable from the 1st day through to 7th day and increased with doses. After the administration, the serum ABK concentrations were decreased with time, and the means of C(trough) were 0.4 microg/mL (LOQ) -0.5 microg/mL, which showed ABK has no tendency toward accumulation. In addition, t1/2, CL(tot), CL(r) V(ss) and urinary excretion were constant throughout administration days at either dose, and CL(tot) containing CL(r) was not decreased. There were no notable changes in the functions of the kidney, auditory organs, etc. Based on the above-mentioned results, when ABK 400 or 600 mg was intravenously administered over 30 min once or once a day for 7 days to the healthy male volunteers with normal renal clearance, it is suggested there were no problems in terms of safety, and C(max) were 36.7-54.1 and 44.2-78.5 microg/mL, respectively. In addition, C(trough) was 0.5 microg/mL or lower at either doses and ABK was not accumulated in multiple administration of ABK. ABK was, therefore, expected to have good safety profile and favorable pharmacokinetics.

Pharmacokinetic study on acetoside in rats

To establish a HPLC method for determining acetoside in rat plasma and to investigate the pharmacokinetic characteristics of acetoside in rats. Six rats were orally administered with 150 mg x kg(-1) acetoside and their blood samples were collected at different time points. The plasma concentration of acetoside was determined by reserved HPLC, and the pharmacokinetic parameters were calculated by DAS 2.0 software. The regression equation of acetoside in rats plasma was Y = 3.509 8X-0.096 8 (r = 0.996 8), which showed a good linear relation at 0.125-2.5 mg x L(-1). The method showed a recovery of more than 85%, and both inter-day and intra-day RSDs were less than 15%. After the oral administration of 150 mg x kg(-1) acetoside, the concentration-time curves of acetoside were expressed in a open two-compartment model. The main pharmacokinetics parameters of T(max), C(max), t(1/2alpha), t(1/2beta), AUC(0-t), AUC(0-infinity), CL/F, V/F and K(a) were respectively 0.36 h, 1.126 mg x L(-1), 0.759, 4.842 h, 3.134, 3.766 mg x h x L(-), 87.089 L x h(t) x kg(-1), 207.704 L x kg(-1) and 6.345 h(-1) respectively. It is first time to establish such a HPLC method to determine the concentration of acetoside in plasma. The method is so highly specified and sensitive that it can ble used in quantitative analysis in vivo on acetoside.

Comparison on in vivo pharmacokinetics of brucine, total alkaloids of Strychni Semen and Strychni Semen pulveratum in rats

To study different in vivo pharmacokinetic regularity of brucine, total alkaloids of scorched sand-prepared Strychni Semen products and Strychni Semen pulveratum in rats, and probe into mutual impact between single component and compound. Rats in each group were orally administered with brucine, total alkaloids of scorched sand-prepared Strychni Semen products and Strychni Semen pulveratum suspension. The in vivo plasma concentrations of brucine in rats were determined by HPLC. A compartment model was made for the blood drug concentration-time curve using 3P97 software package and the pharmacokinetic parameters of each group were calculated and compared. The in vivo metabolic process of brucine in rats complied with the two-compartment model, weight W = 1/C2. The results of variance analysis showed that among three existing forms of brucine with same dosage, the brucine solution group and the total alkaloids group of scorched sand-prepared Strychni Semen products showed significant differences in C(max), MRT (P < 0.05); and the brucine solution group and the Strychni Semen pulveratum suspension group showed significant differences in C(max), AUC(0-t), and AUC(0-infinity), in which the latter displayed minimum C(max), AUC(0-t) and AUC(0-infinity). The total alkaloids group of scorched sand-prepared Strychni Semen products showed a relatively longer retention time of effective components of brucine in plasma, while the Strychni Semen pulveratum suspension group showed a lower bioavailability.

Comparative pharmacokinetics study of astilbin after oral administration of Yinxieling prescription or Smilacis Glabrae Rhizoma to rats

To establish a SPE-HPLC method for analyzing astilbin in rats serum and explore the effects of Yinxieling (YXL) prescription and Smilacis Glabrae Rhizoma on the pharmacokinetic characteristics of effective components. Male Sprague-dawley rats were administrated YXL and Smilacis Glabrae Rhizoma respectively. At different time points, serum concentration of astilbin was extracted by Solid Phase Extraction (SPE) and determined using HPLC method. Chromatographic separation was achieved on a reversed-phase Phenomenex C18 column with the mobile phase of methanol-acetonitrile-formic acid water solution (0.05% formic acid) and gradient elution, temperature of bar was 24 degrees C, flow rate was 0.8 mL x min(-1). The method showed excellent linearity over the concentration range 0.266-53.1 mg x L(-1) of astilbin (r = 0.996). The extract recoveries were from 79.0% to 89.1%. Significant diffenerce in pharmacokinetic parameter of astilbin including t1/2, Cmax, AUC(0-t), AUC(0-infinity) and MRT were obtained through non-compartment model after oral administration of YXL prescription comparing with Smilacis Glabrae Rhizoma. The method was applied to a pharmacokinetic study of astilbin. It indicated that the bioavailability of astilbin in YXL enhanced in rats and one of the reasons may be that components of prescription affect the pharmacokinetics of astilbin in vivo.

Quantification of Nimesulide in Human Plasma by High-Performance Liquid Chromatography with Ultraviolet Detector (HPLC-UV): Application to Pharmacokinetic Studies in 28 Healthy Korean Subjects

Nimesulide is a selective COX-2 inhibitor that is as effective as the classical non-acidic nonsteroidal anti-inflammatory drugs in the relief of various pain and inflammatory conditions, but is better tolerated with lower incidences of adverse effects than other drugs. After oral dose of 100 mg nimesulide to western subjects, a mean maximal concentration (C(max)) of 2.86 ∼ 6.5 µg/mL was reached at 1.22 ∼ 2.75 h and mean t(1/2β) of 1.8 ∼ 4.74 h. This study developed a robust method for quantification of nimesulide for the pharmacokinetics and suitability of its dosage in Korea and compared its suitability with other racial populations. Nimesulide and internal standard were extracted from acidified samples with methyl tert-butyl ether and analyzed by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). The 28 healthy volunteers took 2 tablets of 100 mg nimesulide and blood concentrations were analyzed during the 24 h post dose. Several pharmacokinetic parameters were represented: AUC(0-infinity) = 113.0 mg-h/mL, C(max) = 12.06 mg/mL, time for maximal concentrations (T(max)) = 3.19 h and t(1/2β) = 4.51 h. These were different from those of western populations as follows: AUC was 14.5% and C(max) was 28% that of of Korean subjects and T(max) and t(1/2β) were also different. The validated HPLC-UV method was successfully applied for the pharmacokinetic studies of nimesulide in Korean subjects. Because the pharmacokinetics of nimesulide were different from western populations, its dosage regimen needs to be adjusted for Koreans.

Determination of brucine and strychnine in rat after cutaneous administration of Semen Strychni niosome gel by LC-MS/MS

A sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the determination of brucine and strychnine in rat plasma. Samples were extracted by ethyl acetate-n-butanol (7: 3). Chromatographic separation was operated on ZORBAX XDB-C18 column with gradient elution of acetonitrile-methanol-water (0.05% acetic acid and 10 nmol x L(-1) ammonium formate contained), followed by LC-MS/MS in positive electrospray ionization. Quantification was carried out on multiple reaction monitoring (MRM) of the transition m/z 395.2/324.2, m/z 335.2/184.2 and m/z 199.1/171.1 for brucine, strychnine and tacrine (internal standard), respectively. The method was linear in the range of 0.195-100 and 0.07840 microg x L(-1) for brucine and strychnine, with coefficient correlation 0.994 and 0.996 respectively. The recoveries of extraction were 78.9% - 102.4% for brucine and 95.2% - 106.1% for strychnine. Precision, accuracy, stability and matrix effect of the analytes met the requirement. The method was applied to a pharmacokinetic study of brucine and strychnine after cutaneous administration of Semen Strychni niosome gel. The C(max) were (26.20 +/- 5.81) and (12.50 +/- 3.00) microg x L(-1) while the AUC(0-infinity), were (193.75 +/- 39.43) and (98.25 +/- 28.54) microg x h x L(-1) of the two components. We conclude that the niosomes may reduce the systemic exposures and prolong the local release of brucine and strychnine.

Comparative pharmacokinetic and relative bioavailability study of coated and uncoated azithromycin powder for suspension in healthy Bangladeshi male volunteers

Azithromycin (AZT; CAS 83905-01-5) is an efficient antibiotic and is widely prescribed in Bangladesh. The taste of uncoated AZT suspension is bitter. Although several taste masked oral suspensions of AZT are available in Bangladesh, information regarding the bioavailability of these formulations in Bangladeshi population is unavailable. The purpose of this study was to compare the relative bioavailability and other pharmacokinetic properties of two oral formulation of AZT (200 mg/5 ml) suspensions, the uncoated reference product and coated test product (Tridosil 200 mg/5 ml) and to evaluate whether these formulations meet the FDA criteria to assume bioequivalence in Bangladeshi male volunteers. A randomized, single-dose, two-way cross-over, open-label pharmacokinetic study was conducted in 24 healthy male volunteers after administration of a single dose of 500 mg AZT suspension under fasting condition following a washout period of three weeks. Blood samples were collected in different time intervals and analyzed for serum AZT concentration using a validated LC/MS/MS method. The pharmacokinetic parameters were determined by the non-compartmental method. From serum data, the obtained values for test and reference products were 383.21 +/- 11.59 and 432.28 +/- 7.22 ng/ ml for Cmax; 5677.47 +/- 1229.53 and 6144.56 +/- 1098.70 h x ng/ml for AUC(0-120); and 6085.29 +/- 1267.53 and 6694.15 +/- 1222.50 h x ng/ml for AUC(0-infinity), respectively. On analysis of variance, no period or sequence effects were observed for any pharmacokinetic property; however, a significant formulation effect was observed for Cmax and AUMC(0-infinity). The 90% confidence intervals of the test formulation/reference mean ratios of the Intransformed Cmax, AUC(0-120) and AUC(0-infinity) mean values were found to be 87.89% to 89.36%, 87.96% to 95.71% and 86.77% to 94.29% respectively. In this single-dose study of AZT, it was found that the test formulation met the regulatory criteria for bioequivalence to the reference suspension formulation.

Comparative in vitro dissolution and in vivo bioequivalence of two diclofenac enteric coated formulations

The aim of this study was the comparison of in vitro dissolution and in vivo bioavailability of two different brands of diclofenac sodium (CAS 15307-86-5) enteric coated tablets in healthy male Iranian volunteers in a single-dose, randomized, open-label, single blind study, which was conducted according to a crossover design in healthy volunteers. A washout interval of two weeks was selected between administrations to each subject in this study. Serial venous blood samples over 10 h after each administration to measure diclofenac sodium concentration in serum were obtained, and placed into tubes containing sodium heparin. Then the plasma was separated and kept frozen at -20 degrees C for subsequent analysis with a modified HPLC method with UV detection. In addition, the in vitro dissolution study was performed on the brands. For the test and reference formulation, mean Cmax values were 2257.3 (ng/ml) and 2156 (ng/ml), respectively. The mean AUC(0)tau and AUC(0)infinity were 5726.1 (ng x h/ml) and 5917.8 (ng x h/ml) for the test and 5689.9 (ng x h/ml) and 5967.4 (ng x h/ml) for the reference formulation, respectively. Results show that the 90% confidence intervals for the ratio of test and reference products in Cmax (101.4-114.9%), AUC(0)tau (96.3-109.1%) and AUC(0)infinity (94.7-107.3%) were all within the 80-125% interval proposed by the FDA and EMA. Both formulations released > 80% of drug within 30 min in buffer pH = 6.8 medium. Therefore the diclofenac sodium enteric coated tablets of the test and reference formulations are bioequivalent in terms of rate and extent of absorption.

Study on pharmacokinetics of danshensu sodium in danshen dripping solution in Beagles

To detect pharmacokinetics of Danshensu Sodium in Danshen dripping solution in Beagles. Danshen dripping solution was dripped intravenously into healthy Beagles at a dose of 10 mL x kg(-1). Their plasma samples were extracted with acetic ether, the blood concentrations were determined by HPLC method. Danshensu Sodium showed a good linear relationship within the range of 0.225-18.000 mg x L(-1), with the lowest detectable limit of 0.113 mg x L(-1). Its pharmacokinetic parameters were as follows: tmax was 30 min, Cmax was (9.5742 +/- 2.3715) mg x L(-1), t1/2 was (19.23 +/- 2.97) min, CL was (0.0127 +/- 0.0030) L x min(-1) x kg(-1), AUC(0-tn) was (474.954 +/- 95.483) mg x min x L(-1) and AUC(0-infinity) was (482.494 +/- 95.353) mg x min x L(-1). The accurate, stable and reliable blood concentration method shows a one-compartment mode of Danshensu Sodium in Beagles.