• 한국임상약학회지
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• 제7권2호
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• pp.51-63
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• 1997

The effect of cimetidine administration on the pharmacokinetic parameters of cyclosporine were determined in healthy voluteers. This study was performed in 10 volunteers of age ranged 22-48 years and body weight 48-62 kg. This study was performed with cross-over design. Mono cyclosporine and cyclosporine metabolites was extracted from whole blood analysed by fluororescence polarization immune assay (TDX-FLX, Abbott). After coadministration of cimetidine (300 mg) with cyclosporine (300 mg) orally, maximum concentration of mono cyclosporine was significantly increased $1221{\pm}143\;ng/ml\;to\;1562{\pm}184\;ng/ml$ (P<0.05), area under the time curve of cyclosporine (12 hr) also was significantly increased $7478{\pm}829\;ng/ml{\cdot}hr\;to\;9721{\pm}879\;ng/ml{\cdot}hr$ (P<0.05) and absolute baioavailability of cyclosporine was increased $50\pm5.6\%\;to\;57.6\pm6.1\%\;(P<0.05)$ compared to control group. The blood concentrations of cyclopsorine metabolites were significantly decrased (P<0.05) after coadministration of cimetidine. In cimetidine pretreated group, blood mono cyclosporine concentrations were increased significan시y $1220.0\pm203.00\;ng/ml\;to\;1510.0\pm204.00\;ng/ml$ compared with control group (P<0.05). In the mono cyclosporine pharmacokinetic parameter after oral administration absorption rate and maximum concentration were significantly higher in cimetidine coadministered and pretreated group than control group (P<0.05). The ratio of metabolites and mono cyclosporine concentrations was decreased significantly from $70.8\%\;in\;control\;to\;34.8\%$ in coadministration of cimetidine orally. As matter of facts these reults are considered to inhibition of cyclosporine hepatic metabolism and increasing of cyclosporine absorption rate in gastrointestinal tract because of maintaining cyclosporine stability in elevated gastric pH by cimetidine. We considered, it appeares that cimetidine increase bioavailability of cyclosporine by increasing oral absorption and by decreasing hepatic clearance. But the absorption and clearance of cyclosporine was highly variable individually, and therefore we consider that cyclosporine blood level monitoring would be essential in patients with cimetidine co-administration.

• 한국임상약학회지
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• 제21권3호
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• pp.224-227
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• 2011

Entecavir is a potent and selective guanosine analogue that has demonstrated a significant antiviral efficacy against hepatitis B virus (HBV). The aim of this study was to evaluate the safety and pharmacokinetic profile after a single dose of entecavir 1 mg administration in Korean healthy male subjects. Eight volunteers were enrolled. After a single dose of 1 mg entecavir was orally administered, blood samples were collected at specific time intervals from 0-168 hours. The plasma concentrations of entecavir were determined by LC-MS/MS. The pharmacokinetic parameters were determined from the plasma concentration-time profiles. The mean values for $AUC_{last}$ and $AUC_{inf}$ were $14.84{\pm}7.81ng{\cdot}hr/mL$ and $20.71{\pm}8.80ng{\cdot}hr/mL$, respectively. The mean value for $C_{max}$ was $9.19{\pm}4.91ng/ml$ and median value for $t_{max}$ was 0.58 hr. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. The results are suggested to be useful in clinical trials of entecavir in Korean subject including bioequivalence study.

• Biomolecules & Therapeutics
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• 제17권3호
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• pp.311-317
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• 2009

Ginkgo biloba (G. biloba) extract is a widely used phytomedicine for the oral treatment of peripheral vascular disease. Cilostazol is a synthetic antiplatelet and vasodilating agent for the treatment of intermittent claudication resulting from peripheral arterial disease. It is likely to use concomitantly G. biloba extract and cilostazol for the treatment of peripheral arterial disease, which raises a concern of increasing their adverse effects of herbal-drug interactions. To clarify any possible herbal-drug interaction between G. biloba extract and cilostazol, the effect of the G. biloba extract on the pharmacokinetics of cilostazol was investigated. As cilostazol is known to be eliminated mainly by cytochrome P450 (CYP)-mediated metabolism, we investigated the effects of G. biloba extract on the human CYP enzyme activities and the effect of G. biloba extract on the pharmacokinetics of cilostazol after co-administration of the two agents to male beagle dogs. The G. biloba extract inhibited more or less CYP2C8, CYP2C9, and CYP2C19 enzyme activities in the in vitro microsomal study with $IC_{50}$ values of 30.8, 60.5, and $25.2{\mu}g/ml$, respectively. In the pharmacokinetic study, co-administration with the G. biloba extract had no significant effect on the pharmacokinetics of cilostazol in dogs, although CYP2C has been reported to be responsible for the metabolism of cilostazol. In conclusion, these results suggest that there may not be a pharmacokinetic interaction between G. biloba extract and cilostazol.

• Journal of Pharmaceutical Investigation
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• 제41권5호
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• pp.289-294
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• 2011

A rapid and specific high performance liquid chromatography-tandem mass (LC/MS/MS) method for the analysis of montelukast in human plasma has been developed and validated. After cold acetonitrile-induced precipitation of the plasma samples, montelukast and glipizide (internal standard, IS) were eluted on a reverse-phase $C_{18}$ column by isocratic mobile phase consisted of 10 mM ammonium formate buffer (adjusted to pH 3.5 with formic acid) and acetonitrile (3:97, v/v). Acquisition was performed with multiple reaction monitoring (MRM) mode by monitoring the transitions: m/z 587.2${\rightarrow}$ 423.2 for montelukast and m/z 446.0${\rightarrow}$321.2 for IS. Ranges of concentration for calibration curves (10-1000 ng/mL) showed correlation coefficients ($r^2$) were better than 0.9948. Precision of intra- and inter-day ranged from 3.70 to 11.68% and from 3.04 to 12.95%, accuracy of intra-day and inter-day ranged from 93.34 to 102.75% and from 100.79 to 107.63%, respectively. The described method provides a fast and sensitive analytical tool for determining montelukast levels in plasma, and was successfully applied to a pharmacokinetic study in 16 healthy human subjects after oral administration of 10mg tablet formulation of montelukast sodium under fasting conditions.

• Bulletin of the Korean Chemical Society
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• 제34권8호
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• pp.2425-2430
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• 2013

A simple, fast and robust analytical method was developed to determine imatinib in human plasma using liquid chromatography-tandem mass spectrometry with electrospray ionization in the positive ion mode. Imatinib and labeled internal standard were extracted from plasma with a simple protein precipitation. The chromatographic separation was performed using an isocratic elution of mobile phase involving 5.0 mM ammonium formate in water-5.0 mM ammonium formate in methanol (30:70, v/v) over 3.0 min on reversed-stationary phase. The detection was performed using a triple-quadrupole tandem mass spectrometer in multiple-reaction monitoring mode. The developed method was validated with lower limit of quantification of 10 ng/mL. The calibration curve was linear over 10-2000 ng/mL ($R^2$ > 0.99). The method validation parameters met the acceptance criteria. The spiked samples and standard solutions were stable under conditions for storage and handling. The reliable method was successfully applied to real sample analyses and thus a pharmacokinetic study in 27 healthy Korean male volunteers.

• Mass Spectrometry Letters
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• 제12권4호
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• pp.200-205
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• 2021

Polynemoraline C, a pyridocoumarin alkaloid, exhibits anticholinergic, anti-inflammatory, antitumor, and antimicrobial activities. A sensitive analytical method of polynemoraline C in mouse plasma was developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Polynemoraline C and ¹³C-caffeine (internal standard) in mouse plasma were extracted using a liquid-liquid extraction method coupled with ethyl acetate. This extraction method resulted in high and reproducible extraction recovery in the range of 73.49%-77.31% with no interfering peaks around the peak retention time of polynemoraline C and ¹³C-caffeine. The standard calibration curves for polynemoraline C were linear over the range of 0.5-200 ng/mL with r² > 0.985. The accuracy, precision, and the stability of the data were within acceptable limits on the FDA guideline. After intravenous and oral administration of polynemoraline C at doses of 5 and 30 mg/kg, respectively, the present method was successfully applied to the pharmacokinetic study of polynemoraline C. Polynemoraline C in mouse plasma showed a multi-exponential elimination pattern with a high volume of distribution values. This compound's absolute oral bioavailability was found to be 17.0%. Polynemoraline C's newly developed LC-MS/MS method can be used for further studies on the efficacy, toxicity, and biopharmaceutics of polynemoraline C, as well as its pharmacokinetic studies.

• Journal of Veterinary Science
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• 제23권5호
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• pp.64.1-64.9
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• 2022

Background: Fluralaner is a novel drug belonging to the isoxazoline class that acts on external parasites of domestic animals. It is used systemically via drinking water, especially against red poultry mite in layer chickens. Fluralaner is frequently used in layers infected with D. gallinae. However, no study to date has investigated the effects of feed intake and water hardness. Objectives: This study aimed to investigate the effects of variable water hardness and feed intake on the pharmacokinetic profile of fluralaner. Methods: Layer chickens were divided into four groups (n = 8): fed + purified water (Group 1), feed restricted + purified water (Group 2), feed restricted + hard water (Group 3), and feed restricted + soft water (Group 4). After administering a single dose of the drug with drinking water, the blood samples were collected for 21 days. Fluralaner concentrations in plasma samples were determined by liquid chromatography/tandem mass spectrometry. The maximum plasma concentration (C_max), time to reach maximum plasma concentration (t_max), area under the concentration-time curve values (AUC_0-21d), half-life (t_1/2), and other pharmacokinetic parameters were calculated. Results: Although the highest maximum plasma concentration (C_max) was determined in Group 1 (fed + purified water), no statistically significant difference was found in the C_max, t_max, t_1/2, MRT_{0-inf_obs}, Vz/F_obs, and Cl/F_{_obs} parameters between the experimental groups. Conclusions: It was concluded that the feed intake or water hardness did not change the pharmacokinetic profile of fluralaner in layer chickens. Therefore, fluralaner could be used before or after feeding with the varying water hardness in poultry industry.

• 한국임상약학회지
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• 제22권1호
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• pp.9-12
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• 2012

Background: Cefcapene pivoxil hydrochloride, is an ester-type oral cephem antibiotic. This study was performed to compare the pharmacokinetics and evaluate the bioequivalence of two cefcapene pivoxil hydrochloride 75 mg formulations. Method: In a randomized $2{\times}2$ crossover study, sixty healthy male volunteers were randomly assigned into two groups. After a single dose of 75 mg cefcapene pivoxil hydrochloride oral administration, blood samples were collected at specific time intervals from 0-12 hours. The plasma concentrations of cefcapene pivoxil hydrochloride were determined by LC-MS/MS. The pharmacokinetic parameters were determined from the plasma concentration-time profiles of both formulations. The pharmacokinetic parameters such as $AUC_{last}$, $AUC_{inf}$ and $C_{max}$, were calculated and the 90% confidence intervals for test/reference ratio for pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data. Results: The mean value for $AUC_{last}$ in test and reference drug was $4053.1{\pm}876.5\;ng{\cdot}hr/mL$ and $3595.7{\pm}1029.1\;ng{\cdot}h/mL$, respectively. The mean value for $C_{max}$ in test and reference drug was $1324.9{\pm}321.4$ ng/mL and $1159.1{\pm}335.9$ ng/mL, respectively. The 90% confidence intervals of the $AUC_{last}$ and $C_{max}$ ratio for test drug and reference drug were log 1.09-log1.22 and log 1.09-log1.24, respectively. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. Conclusion: This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these health volunteers. Both formulations were safe and well tolerated in 75 mg of cefcapene pivoxil hydrochloride.

• Journal of Pharmaceutical Investigation
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• 제35권3호
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• pp.137-142
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• 2005

A rapid, selective and sensitive reversed-phase HPLC method for the determination of glipizide in human serum was validated and applied to the pharmacokinetic study of glipizide. Glipizide and internal standard, tolbutamide, were extracted from human serum by liquid-liquid extraction with benzene and analyzed on a Nova Pak $C_{18}\;60{\AA}$ column with the mobile phase of acetonitrile-potassium dihydrogen phosphate (10 mM, pH 3.5) (4:6, v/v). Detection wavelength of 275 nm and flow rate of 0.7 ml/min were fixed for the study. The assay robustness for the changes of mobile phase pH, organic solvent content, and flow rate was confirmed by $3^3$ factorial design using a fixed glipizide concentration (500 ng/ ml) with respect to its peak area and retention time. And also, the ruggedness of this method was investigated at three different laboratories using same quality control (QC) samples. This method showed linear response over the concentration range of 10-1000 ng/ml with correlation coefficient greater than 0.999. The lower limit of quantitation using 0.5 ml of serum was 10.0 ng/ml, which was sensitive enough for pharmacokinetic studies. The overall accuracy of the quality control samples ranged from 82.6 to 105.0% for glipizide with overall precision (% C.V.) being 1.13-13.20%. The percent recovery for human serum was in the range of 85.2 93.5%. Stability studies showed that glipizide was stable during storage, or during the assay procedure in human serum. The peak area and retention time of glipizide were not significantly affected by the changes of mobile phase pH, organic solvent content, and flow rate under the conditions studied. This method showed good ruggedness (within 15% C.V.) and was successfully used for the analysis of glipizide in human serum samples for the pharmacokinetic studies at three different laboratories, demonstrating the suitability of the method.

• 약학회지
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• 제48권1호
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• pp.1-5
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• 2004

The purpose of this study was to investigate the effect of coadministration and 3 days-pretreatmemt of niledipine (2, 10 mg/kg) on the pharmacokinetic parameters and bioavailability of paclitaxel (50 mg/kg) after oral administration in rats. Coadministration of nifedipine with paclitaxel did alter the $C_{max}$ (115${\pm}$29 ng/ml without nifedipine; 135${\pm}$35 ng/ml with nifedipine (10 mg/kg): p<0.05) and AUC (188${\pm}$459 ng/mlㆍhr with-out nifedipine; 2546${\pm}$642 ng/mlㆍhr with nifedipine; p<0.05). Three days treatment of nifedipine on the prior to paclitaxel administration increased the $t_{1/2}$ 〔9.90${\pm}$2.47 hr without nifedipine; 12.37${\pm}$3.12 hr with nifedipine (2 mg/kg): 12.83${\pm}$3.32 hr with nifedipine (10 mg/ml); p<0.05] and AUC [1833${\pm}$459 ng/mlㆍhr without nifedipine; 2663${\pm}$648 ng/mlㆍhr with nifedipine (2 mg/kg): 3006${\pm}$734 ng/mlㆍhr with nifedipine (10 mg/ml): p <0.05]. Drug interaction between nifedipine and paclitaxel decreased the elimination rate constant and increased the oral bioavailability of paclitaxel. On the basis of the results of this study, it might be considered that nifedip ine may inhibit cytochrome P450, which are engaged in paclitaxel metabolism, result in increased $t_{1/2}$ and AUC of paclitaxel. However, further study should be conducted to clarify the roles of cytochrome P450 and P-glycoprotein on paclitaxel bio-availability wit/or without nifedipine.