Objective We analyzed differences between spontaneously reported drug-induced (not including cont... more Objective We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions. Methods Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary's teaching hospital, Daejeon, Korea) from 2010-2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton's preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed. Results Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reactionassociated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast mediainduced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions PLOS ONE |
The Journal of allergy and clinical immunology, 2014
Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic resp... more Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on FcεRI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK1/2-mediated positive and the AMPK-mediated negative regulation of FcεRI signaling in mast cells. We investigated possible interactions between ERK1/2 and AMPK in the modulation of mast cell signaling and anaphylaxis. Wild-type or AMPKα2(-/-) mice, or bone marrow-derived mast cells obtained from these mice, were treated with either chemical agents or small interfering RNAs that modulated the activity or expression of ERK1/2 or AMPK to evaluate the functional interplay between ERK1/2 and AMPK ...
The clinical utility of anthracyclines like idarubicin (IDA) is limited by the occurrence of mult... more The clinical utility of anthracyclines like idarubicin (IDA) is limited by the occurrence of multidrug resistance and cardiotoxicity. Previous studies have demonstrated that the multidrug transporter P-glycoprotein (P-gp) is present in the heart and have suggested that it exerts a protective function. We sought to determine the influence of P-gp inhibitors verapamil and PSC 833 on myocardial uptake, metabolism, and actions of IDA. Methods. In Langendorff-perfused rat hearts, the outflow concentration-time curve and the residual amount in cardiac tissue of IDA and its active metabolite idarubicinol (IDOL) were measured after 0.5 mg dose of IDA in the absence and presence of the P-gp inhibitors verapamil and PSC 833. Results. During perfusion (80 min), 2% of the IDA dose was converted to IDOL in the heart. Myocardial uptake of IDA was significantly increased by verapamil but not by PSC 833, which increased the recovery of IDA and IDOL. IDA significantly decreased left ventricular developed pressure to approximately 40% and increased coronary vascular resistance to 140% of baseline level, respectively. The vasoconstrictive effect was markedly potentiated by PSC 833. Conclusions. The enhancement of myocardial IDA uptake by verapamil could be due to a decrease in P-gp-mediated efflux. PSC 833 inhibits cardiac metabolism (non-IDOL pathways) and increases the acute cardiotoxicity of IDA.
Journal of pharmaceutical and biomedical analysis, 2014
7-O-Succinyl macrolactin A (SMA) and its major metabolite macrolactin A (MA) are generated from B... more 7-O-Succinyl macrolactin A (SMA) and its major metabolite macrolactin A (MA) are generated from Bacillus polyfermenticus KJS-2. Both substances show inhibitory effects on angiogenesis and cancer cell invasion. SMA in rat plasma is known to be relatively stable at room temperature, but MA was not detected due to its instability. Therefore, a stabilizer is required to accurately measure the substance in biological rat samples. In this study, NaF and eserine were examined to determine whether they could stabilize MA to allow for accurate measurement in rat plasma. We also developed a rapid and simple chromatographic method using tandem mass spectrometry (MS/MS) for the simultaneous determination of these compounds in rat plasma. After simple protein precipitation with acetonitrile including methaqualone (internal standard), the analytes were chromatographed on a Hilic column with a mobile phase of 10mM formic acid aqueous solution, methanol, and acetonitrile (15:15:70, v/v). The accura...
Scutellaria baicalensis is one of the most widely used herbal medicines in East Asia. Because bai... more Scutellaria baicalensis is one of the most widely used herbal medicines in East Asia. Because baicalein and baicalin are major components of this herb, it is important to understand the effects of these compounds on drug metabolizing enzymes, such as cytochrome P450 (CYP), for evaluating herb-drug interaction. The effects of baicalin and baicalein on activities of ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), benzyloxyresorufin O-debenzylase (BROD), p-nitrophenol hydroxylase and erythromycin N-demethylase were assessed in rat liver microsomes in the present study. In addition, the pharmacokinetics of caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) in baicalin-treated rats were compared with untreated control. As results, EROD, MROD and BROD activities were inhibited by both baicalin and baicalein. However, there were no significant differences in the pharmacokinetic parameters of oral caffeine and its three metabolites between control and baicalin-treated rats. When the plasma concentration of baicalin was determined, the maximum concentration of baicalin was below the estimated IC 50 values observed in vitro. In conclusion, baicalin had no effects on the pharmacokinetics of caffeine and its metabolites in vivo, following single oral administration in rats.
Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongatio... more Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography-mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (.1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-59-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.
The purpose of this study was to construct a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) ... more The purpose of this study was to construct a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for digoxin that describes the relationship between plasma concentration and inotropic response. Methods. On the basis of results obtained in the isolated perfused rat heart, a PK/PD model for digoxin in humans was developed. In fitting the model to previously published bolus dose and concentration clamp data (shortening of electromechanical systole), the plasma concentration-time curves were used as forcing functions in the computer program ADAPT II. Results. The mechanistic approach allowed a modeling of digoxin pharmacodynamics which is consistent with available inotropic response data. The estimates of the receptor binding parameters were in the same order of magnitude as those measured in vitro for ouabain. The mechanistic model explained the parameters of the empirical link model (EC 50 , E max and delay time) in terms of the underlying processes, suggesting that the long equilibration half-time of 13 h is due to slow receptor binding. The empirical link model, in contrast, is not compatible with a noninstantaneous receptor binding process and led to estimates of the delay time that were dependent on the digoxin administration schedule. Conclusions. The new, mechanistic model may provide a rationale for better understanding of digoxin pharmacodynamics and could become a tool to bridge the gap between in vitro and in vivo studies.
Journal of Toxicology and Environmental Health, Part A, 2010
A possible role of metabolism in 1-bromopropane (1-BP)-induced hepatotoxicity was investigated in... more A possible role of metabolism in 1-bromopropane (1-BP)-induced hepatotoxicity was investigated in male ICR mice. The depletion of glutathione (GSH) by formation of GSH conjugates was associated with increased hepatotoxicity in 1-BP-treated mice. The formation of S-propyl and 2-hydroxypropyl GSH conjugates were identified in the liver following 1-BP treatment. In addition, the formation of reactive metabolites of 1-BP by certain cytochrome P-450 (CYP) may be involved in 1-BP-induced hepatotoxicity. The decreased content of hepatic GSH produced by 1-BP was associated not only with increased activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but also with elevated levels of hepatic thiobarbituric acid-reactive substance (TBARS) in mice where metabolic enzymes were induced by pretreatment with phenobarbital. In addition, the hepatotoxicity induced by 1-BP was prevented by pretreatment with SKF-525A. Taken together, the formation of reactive metabolites by CYP and depletion of GSH may play important roles in hepatotoxicity induced by 1-BP.
Journal of Toxicology and Environmental Health, Part A, 2009
Tetrabromobisphenol A (TBBPA), one of the most widely used global brominated flame retardants, is... more Tetrabromobisphenol A (TBBPA), one of the most widely used global brominated flame retardants, is used to improve fire safety of laminates in electrical and electronic equipment. To investigate the nephrotoxic potential of TBBPA and its toxicokinetic profile in rats, single-dose and daily 14-d repeated-dose toxicity studies at 200, 500, or 1000 mg/kg were performed. Several biochemical parameters were analyzed to evaluate nephrotoxicity of TBBPA. High-dose 1000 mg/kg TBBPA significantly elevated renal thiobarbituric acid-reactive substance (TBARS) levels, and superoxide dismutase (SOD) activity was increased at all 3 doses administered. This was associated with no change in the activity of catalase (CAT). Our results suggest that acute 1-d high-dose administration of TBBPA produced transient renal changes at 5 h. Subsequently, TBBPA in serum, urine, and kidney was determined by liquid chromatography-mass spectroscopy (LC/MS). Toxicokinetic studies indicated that TBBPA shows relatively a short half-life (7-9 h) and was eliminated almost completely in feces by 2 d. Based on the results from the 14-d repeated-dose study, TBBPA did not accumulate in the rat, and was eliminated in feces. The present results suggested that TBBPA may not be toxic to kidney, as the chemical is not bioavailable and is not present in renal tissue.
We developed a method for the simultaneous quantification of aceclofenac and its three major meta... more We developed a method for the simultaneous quantification of aceclofenac and its three major metabolites in rat plasma. After protein precipitation with acetonitrile including flufenamic acid as an internal standard (IS), aceclofenac, diclofenac, 4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-hydroxyaceclofenac, 4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-hydroxydiclofenac, and the IS were chromatographed on a reverse-phase C18 analytical column. The isocratic mobile phase of acetonitrile/0.1% formic acid (aq; 9:1 [v/v]) was eluted at 0.3 mL/min. Quantification was performed on a triple-quadrupole mass spectrometer using electrospray ionization, and the ion transitions were monitored in selective reaction-monitoring mode. The coefficient of variation in the assay precision was less than 8%, and the accuracy was 92-103%. This method was successfully used to measure the concentrations of aceclofenac and its three major metabolites in rat plasma following the oral administration of a single 20 mg/kg oral dose of aceclofenac.
Journal of Pharmacology and Experimental Therapeutics, 2002
Little is known about cardiac uptake kinetics of idarubicin, including a possible protective role... more Little is known about cardiac uptake kinetics of idarubicin, including a possible protective role of P-glycoprotein (Pgp)mediated transport. This study therefore investigated uptake and negative inotropic action of idarubicin in the single-pass isolated perfused rat heart by using a pharmacokinetic/pharmacodynamic modeling approach. Idarubicin was administered as a 10-min constant infusion of 0.5 mg followed by a 70-min washout period in the absence and presence of the Pgp antagonists verapamil or amiodarone. Outflow concentration and left ventricular developed pressure were measured and the model parameters were estimated by simultaneous nonlinear regression. The results indicate the existence of a saturable, Michaelis-Menten type uptake process into the heart (K m ϭ 3.06 M, V max ϭ 46.0 M/min). Verapamil and amiodarone significantly enhanced the influx rate (V max increased 1.8-fold), suggesting that idarubicin is transported by Pgp directly out of the membrane before it gets into the cell. Verapamil and amiodarone attenuated the negative inotropic action of idarubicin, which was linked to the intracellular concentration of idarubicin.
Journal of Pharmaceutical and Biomedical Analysis, 2011
Daumone, 6-(3,5-dihydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-heptanoic acid is a pheromone secret... more Daumone, 6-(3,5-dihydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-heptanoic acid is a pheromone secreted by Caenorhabditis elegans, and has been known as a pivotal regulator of chemosensory processes in development and ageing. A quantification method using mass spectrometry was developed for the determination of daumone in rat plasma. After simple protein precipitation with acetonitrile including an internal standard, the analytes were chromatographed on a reversed-phase column and detected by liquid chromatography/tandem mass spectrometry with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for validation of bioanalytical methods. This method was applied to measure the plasma daumone concentrations after a single intravenous administration of daumone in rats.
Hepatotoxic and immunotoxic effects of 1-bromohexane (1-BH) and its conjugation with glutathione ... more Hepatotoxic and immunotoxic effects of 1-bromohexane (1-BH) and its conjugation with glutathione (GSH) were investigated in female BALB/c mice. The animals were treated once orally with 1-BH at 500, 1000, and 2000 mg/kg in corn oil for a dose-response study or treated orally with 1-BH at 2000 mg/kg for 6, 12, 24, and 48 hr for a time-course study. Treatment with 1-BH increased serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) dose dependently. The hepatic contents of thiobarbituric acid reactive substances were significantly increased at 2000 mg/kg of 1-BH from 12 to 24 hr after the treatment. Oral 1-BH at 2000 mg/kg significantly suppressed production of splenic intracellular interleukin (IL)-2 in response to concanavalin A. Following treatment with 1-BH, three GSH conjugates such as S-hexyl GSH, S-hexyl cysteine, and hydroxyhexyl mercapturic acid were identified in livers by liquid chromatography-electrospray ionization tandem mass spectrometry. The hepatic contents of GSH were maximally decreased 6 hr after treatment with 1-BH. GSH conjugates were also detected maximally in livers 6 hr after treatment. These results suggest that 1-BH could cause hepatotoxicity and immunotoxicity as well as depletion of GSH content due to the formation of GSH conjugates with 1-BH in female BALB/c mice.
We used a novel chromatographic method to rapidly and simply characterize the pharmacokinetics of... more We used a novel chromatographic method to rapidly and simply characterize the pharmacokinetics of benidipine enantiomers in human plasma. The stereoisomers of benidipine were extracted from plasma using diethylether under alkaline conditions. After evaporating the organic layer, the residue was reconstituted in the mobile phase (methanol:acetic acid:triethylamine, 100:0.01:0.0001, v/v/v). The enantiomers in the extract were separated on a macrocyclic antibiotic (Vancomycin) chiral stationary phase column. The mobile phase was eluted at 1 ml/min and was split by an interface. One-fifth of the eluent was used to quantify both isomers in a tandem mass spectrometer in multiple reactionmonitoring mode. The coefficient of variation of the precision of the assay was less than 8%, the assay accuracy was between 93.4 and 113.3%, and the limit of detection was 0.05 ng/ml for 1 ml of plasma. The method described above was used to measure the concentration of both benidipine enantiomers in plasma from healthy subjects who received a single oral dose of a racemate of 8 mg benidipine. The C max and AUC inf values of (+)-alpha benidipine were higher than those of (−)-alpha benidipine by 1.96-and 1.85-fold, respectively (p < 0.001), whereas, the T max and t 1/2 for each of the benidipine stereoisomers were not significantly different.
We evaluated the herb-drug interaction potential of Galgeun-tang (GGT) extracts, mediated by cyto... more We evaluated the herb-drug interaction potential of Galgeun-tang (GGT) extracts, mediated by cytochrome P450 (CYP) inhibition/induction. Further, the effects of fermentation on the CYP-mediated herb-drug interaction potential of GGT extracts were determined. As measured by LC-ESI/MS/MS, GGT extracts (0-300μg/mL) showed no inhibitory activity toward eight CYP isoforms (1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) in pooled human liver microsomes, suggesting that GGT may have low potential for herb-drug interactions mediated by CYP inhibition. Hepatic CYP expression and activity in rats treated with GGT extracts twice per day for 1week was examined. Among the tested CYP isoforms (1A1, 1A2, 1B1, 2B1, 2C11, 2E1, 3A1, 3A2, and 4A1), CYP1B1 and 4A1 were increased by GGT extracts. Hepatic activities of 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase, but not midazolam hydroxylase were also elevated. These results raise the possibility that GGT extracts may increase the toxicity of environmental toxicants through the elevating CYP-dependent metabolic activation. Interestingly, the increases in CYP1B1 and CYP4A1 levels, and 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase activities were attenuated by fermentation of GGT extract using Lactobacillus plantarum KFRI 402, but not 144. Further studies are needed to identify the CYP regulatory component(s) from GGT and determination its metabolism.
Purpose Talniflumate was designed as a prodrug of niflumic acid, a potent analgesic and anti-infl... more Purpose Talniflumate was designed as a prodrug of niflumic acid, a potent analgesic and anti-inflammatory drug, which is widely prescribed for treating rheumatoid diseases. The prandial effect on talniflumate absorption remains unclear; therefore, this study investigated the effect of food on the systemic exposure to niflumic acid in healthy volunteers. Methods Volunteers received a single 740-mg dose of talniflumate 30 min after consuming a high-fat breakfast, a low-fat breakfast, or no food (fasting condition). Plasma concentrations of both talniflumate and niflumic acid were measured using validated high-performance liquid chromatography coupled to tandem mass spectrometry. Results The maximum concentration of niflumic acid was 224±193 ng/ml at ∼2.7 h in the fasted condition compared with 886±417 ng/ml (p<0.05) at 1.8 h and 1,159±508 ng/ml (p<0.01) at 2.2 h with the low-and high-fat meals, respectively. The mean area under the curve from zero to infinity (AUC inf) values after the low-and high-fat meals were four-and fivefold, respectively, the value while fasting (p<0.05). Conclusions It is strongly recommended that talniflumate be taken after a meal to increase systemic exposure to its active metabolite. Our results suggest a reduction in the daily dosage of talniflumate when taken with food.
Background: Clopidogrel, a potent antiplatelet agent, reduces the risk for thrombotic events in p... more Background: Clopidogrel, a potent antiplatelet agent, reduces the risk for thrombotic events in patients with atherothrombotic diseases. Clopidogrel is marketed primarily as a bisulfate salt. A different salt preparation of clopidogrel, clopidogrel besylate, has been developed and might provide an additional treatment option for patients. Objective: The aim of this study was to compare the pharmacokinetic, pharmacodynamic, and tolerability profiles of clopidogrel besylate with those of clopidogrel bisulfate to determine bioequivalence for the purposes of marketing approval. Methods: A randomized, open-label, 2-period, single-and multiple-dose, comparative crossover study was conducted in healthy Korean male subjects. The subjects received either clopidogrel bisulfate or clopidogrel besylate as a single 300-mg oral loading dose (day 1) followed by a 75-mg/d (once daily) maintenance dose on days 2 to 6. After a 15-day washout period, subjects were administered the alternative salt preparation according to the same protocol. The plasma concentrations of clopidogrel and its primary metabolite (SR26334) were assessed using high-performance liquid chromatography/tandem mass spectrometry after administration of the loading dose. The platelet aggregation response to 10-μmol/L adenosine diphosphate was measured using turbidometric aggregometry during the single-and multiple-dosing periods and at steady state (day 6). Tolerability was monitored using physical examination, including vital sign measurements, and laboratory analysis. Results: Forty-four subjects were enrolled and completed the study (mean [SD] age, 24.3 [2.7] years; weight, 70.0 [8.2] kg). The mean values for C max , T max , and AUC 0-t with clopidogrel (parent drug) of clopidogrel besylate (5.2 ng/mL, 0.9 hour, and 10.1 ng/mL/h, respectively) were similar to those with clopidogrel bisulfate (5.4 ng/mL, 0.9 hour, and 10.3 ng/mL/h). The mean values for C max , AUC 0-t , and AUC 0-∞ with the SR26334 of clopidogrel besylate (10.9 μg/mL, 38.8 μg/mL/h, and 43.0 μg/mL/h, respectively) were not significantly different from those with the SR26334 of clopidogrel bisulfate (11.9 μg/mL, 40.6 μg/mL/h, and 43.8 μg/mL/h). The mean values for maximal antiplatelet effect (E max) and area under the time-effect curve (AUEC) with the 2 clopidogrel salt preparations were as follows: clopidogrel besylate, 58.8 h • % and 4299.1 h • % inhibition, respectively; and clopidogrel bisulfate, 61.7 h • % and 4406.9 h • % inhibition; these differences were not statistically significant. The 90% CIs for the ratios of the log-transformed C max , AUC, E max , and AUEC values were within the predetermined bioequivalence range of 80% to 125%. Three adverse events (6.8%) were reported during the study and included abdominal discomfort (1 subject [2.3%] in the group that received clopidogrel bisulfate), easy fatigability (1 subject [2.3%] immediately before administration of loading dose of clopidogrel besylate), and thrombocy
The purpose of this investigation was to develop a method for measuring the concentration of octy... more The purpose of this investigation was to develop a method for measuring the concentration of octylonium in human plasma. Hydrochloric acid was added to the plasma samples before pretreatment to improve the stability of the octylonium. After liquidliquid extraction with ethylacetate ...
A rapid and sensitive method to assay torasemide in plasma was developed using a simple liquid-li... more A rapid and sensitive method to assay torasemide in plasma was developed using a simple liquid-liquid extraction technique followed by high-performance liquid chromatography. Torasemide and the internal standard furosemide were extracted from 0.5 mL of plasma using ethyl acetate in the presence of 0.1M HCl. The analysis of the extracts was performed on a monolithic silica column with ultraviolet spectrophotometric detection. The calibration curve was linear over the concentration range of 0.05-5 lg mL)1 in plasma. Recoveries were reasonable for routine analyses (>80%); the limit of quantification was 0.05 lg mL)1 with a signal-to-noise ratio of 5. The coefficient of variation of the assay precision was less than 6.1%, and the accuracy exceeded 98%. This method was used to measure the torasemide concentration in plasma from healthy subjects after a single 20-mg oral dose of torasemide. This method provides a very simple, sensitive, and accurate way to determine torasemide concentrations in plasma.
Cefetamet is a potent antibiotic to treat respiratory and urinary tract infections. To improve or... more Cefetamet is a potent antibiotic to treat respiratory and urinary tract infections. To improve oral bioavailability, it is administered as a prodrug, cefetamet pivoxyl hydrolyzed by esterase following absorption. A quantification method using a mass spectrometry was developed for the determination of cefetamet in human plasma. After a protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase C₁₈ column and detected by a tandem mass spectrometer with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This method was used to measure the concentrations of the cefetamet in plasma after a single oral administration of 500 mg cefetamet pivoxyl.
Objective We analyzed differences between spontaneously reported drug-induced (not including cont... more Objective We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions. Methods Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary's teaching hospital, Daejeon, Korea) from 2010-2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton's preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed. Results Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reactionassociated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast mediainduced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions PLOS ONE |
The Journal of allergy and clinical immunology, 2014
Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic resp... more Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on FcεRI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK1/2-mediated positive and the AMPK-mediated negative regulation of FcεRI signaling in mast cells. We investigated possible interactions between ERK1/2 and AMPK in the modulation of mast cell signaling and anaphylaxis. Wild-type or AMPKα2(-/-) mice, or bone marrow-derived mast cells obtained from these mice, were treated with either chemical agents or small interfering RNAs that modulated the activity or expression of ERK1/2 or AMPK to evaluate the functional interplay between ERK1/2 and AMPK ...
The clinical utility of anthracyclines like idarubicin (IDA) is limited by the occurrence of mult... more The clinical utility of anthracyclines like idarubicin (IDA) is limited by the occurrence of multidrug resistance and cardiotoxicity. Previous studies have demonstrated that the multidrug transporter P-glycoprotein (P-gp) is present in the heart and have suggested that it exerts a protective function. We sought to determine the influence of P-gp inhibitors verapamil and PSC 833 on myocardial uptake, metabolism, and actions of IDA. Methods. In Langendorff-perfused rat hearts, the outflow concentration-time curve and the residual amount in cardiac tissue of IDA and its active metabolite idarubicinol (IDOL) were measured after 0.5 mg dose of IDA in the absence and presence of the P-gp inhibitors verapamil and PSC 833. Results. During perfusion (80 min), 2% of the IDA dose was converted to IDOL in the heart. Myocardial uptake of IDA was significantly increased by verapamil but not by PSC 833, which increased the recovery of IDA and IDOL. IDA significantly decreased left ventricular developed pressure to approximately 40% and increased coronary vascular resistance to 140% of baseline level, respectively. The vasoconstrictive effect was markedly potentiated by PSC 833. Conclusions. The enhancement of myocardial IDA uptake by verapamil could be due to a decrease in P-gp-mediated efflux. PSC 833 inhibits cardiac metabolism (non-IDOL pathways) and increases the acute cardiotoxicity of IDA.
Journal of pharmaceutical and biomedical analysis, 2014
7-O-Succinyl macrolactin A (SMA) and its major metabolite macrolactin A (MA) are generated from B... more 7-O-Succinyl macrolactin A (SMA) and its major metabolite macrolactin A (MA) are generated from Bacillus polyfermenticus KJS-2. Both substances show inhibitory effects on angiogenesis and cancer cell invasion. SMA in rat plasma is known to be relatively stable at room temperature, but MA was not detected due to its instability. Therefore, a stabilizer is required to accurately measure the substance in biological rat samples. In this study, NaF and eserine were examined to determine whether they could stabilize MA to allow for accurate measurement in rat plasma. We also developed a rapid and simple chromatographic method using tandem mass spectrometry (MS/MS) for the simultaneous determination of these compounds in rat plasma. After simple protein precipitation with acetonitrile including methaqualone (internal standard), the analytes were chromatographed on a Hilic column with a mobile phase of 10mM formic acid aqueous solution, methanol, and acetonitrile (15:15:70, v/v). The accura...
Scutellaria baicalensis is one of the most widely used herbal medicines in East Asia. Because bai... more Scutellaria baicalensis is one of the most widely used herbal medicines in East Asia. Because baicalein and baicalin are major components of this herb, it is important to understand the effects of these compounds on drug metabolizing enzymes, such as cytochrome P450 (CYP), for evaluating herb-drug interaction. The effects of baicalin and baicalein on activities of ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), benzyloxyresorufin O-debenzylase (BROD), p-nitrophenol hydroxylase and erythromycin N-demethylase were assessed in rat liver microsomes in the present study. In addition, the pharmacokinetics of caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) in baicalin-treated rats were compared with untreated control. As results, EROD, MROD and BROD activities were inhibited by both baicalin and baicalein. However, there were no significant differences in the pharmacokinetic parameters of oral caffeine and its three metabolites between control and baicalin-treated rats. When the plasma concentration of baicalin was determined, the maximum concentration of baicalin was below the estimated IC 50 values observed in vitro. In conclusion, baicalin had no effects on the pharmacokinetics of caffeine and its metabolites in vivo, following single oral administration in rats.
Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongatio... more Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography-mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (.1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-59-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.
The purpose of this study was to construct a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) ... more The purpose of this study was to construct a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for digoxin that describes the relationship between plasma concentration and inotropic response. Methods. On the basis of results obtained in the isolated perfused rat heart, a PK/PD model for digoxin in humans was developed. In fitting the model to previously published bolus dose and concentration clamp data (shortening of electromechanical systole), the plasma concentration-time curves were used as forcing functions in the computer program ADAPT II. Results. The mechanistic approach allowed a modeling of digoxin pharmacodynamics which is consistent with available inotropic response data. The estimates of the receptor binding parameters were in the same order of magnitude as those measured in vitro for ouabain. The mechanistic model explained the parameters of the empirical link model (EC 50 , E max and delay time) in terms of the underlying processes, suggesting that the long equilibration half-time of 13 h is due to slow receptor binding. The empirical link model, in contrast, is not compatible with a noninstantaneous receptor binding process and led to estimates of the delay time that were dependent on the digoxin administration schedule. Conclusions. The new, mechanistic model may provide a rationale for better understanding of digoxin pharmacodynamics and could become a tool to bridge the gap between in vitro and in vivo studies.
Journal of Toxicology and Environmental Health, Part A, 2010
A possible role of metabolism in 1-bromopropane (1-BP)-induced hepatotoxicity was investigated in... more A possible role of metabolism in 1-bromopropane (1-BP)-induced hepatotoxicity was investigated in male ICR mice. The depletion of glutathione (GSH) by formation of GSH conjugates was associated with increased hepatotoxicity in 1-BP-treated mice. The formation of S-propyl and 2-hydroxypropyl GSH conjugates were identified in the liver following 1-BP treatment. In addition, the formation of reactive metabolites of 1-BP by certain cytochrome P-450 (CYP) may be involved in 1-BP-induced hepatotoxicity. The decreased content of hepatic GSH produced by 1-BP was associated not only with increased activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but also with elevated levels of hepatic thiobarbituric acid-reactive substance (TBARS) in mice where metabolic enzymes were induced by pretreatment with phenobarbital. In addition, the hepatotoxicity induced by 1-BP was prevented by pretreatment with SKF-525A. Taken together, the formation of reactive metabolites by CYP and depletion of GSH may play important roles in hepatotoxicity induced by 1-BP.
Journal of Toxicology and Environmental Health, Part A, 2009
Tetrabromobisphenol A (TBBPA), one of the most widely used global brominated flame retardants, is... more Tetrabromobisphenol A (TBBPA), one of the most widely used global brominated flame retardants, is used to improve fire safety of laminates in electrical and electronic equipment. To investigate the nephrotoxic potential of TBBPA and its toxicokinetic profile in rats, single-dose and daily 14-d repeated-dose toxicity studies at 200, 500, or 1000 mg/kg were performed. Several biochemical parameters were analyzed to evaluate nephrotoxicity of TBBPA. High-dose 1000 mg/kg TBBPA significantly elevated renal thiobarbituric acid-reactive substance (TBARS) levels, and superoxide dismutase (SOD) activity was increased at all 3 doses administered. This was associated with no change in the activity of catalase (CAT). Our results suggest that acute 1-d high-dose administration of TBBPA produced transient renal changes at 5 h. Subsequently, TBBPA in serum, urine, and kidney was determined by liquid chromatography-mass spectroscopy (LC/MS). Toxicokinetic studies indicated that TBBPA shows relatively a short half-life (7-9 h) and was eliminated almost completely in feces by 2 d. Based on the results from the 14-d repeated-dose study, TBBPA did not accumulate in the rat, and was eliminated in feces. The present results suggested that TBBPA may not be toxic to kidney, as the chemical is not bioavailable and is not present in renal tissue.
We developed a method for the simultaneous quantification of aceclofenac and its three major meta... more We developed a method for the simultaneous quantification of aceclofenac and its three major metabolites in rat plasma. After protein precipitation with acetonitrile including flufenamic acid as an internal standard (IS), aceclofenac, diclofenac, 4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-hydroxyaceclofenac, 4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-hydroxydiclofenac, and the IS were chromatographed on a reverse-phase C18 analytical column. The isocratic mobile phase of acetonitrile/0.1% formic acid (aq; 9:1 [v/v]) was eluted at 0.3 mL/min. Quantification was performed on a triple-quadrupole mass spectrometer using electrospray ionization, and the ion transitions were monitored in selective reaction-monitoring mode. The coefficient of variation in the assay precision was less than 8%, and the accuracy was 92-103%. This method was successfully used to measure the concentrations of aceclofenac and its three major metabolites in rat plasma following the oral administration of a single 20 mg/kg oral dose of aceclofenac.
Journal of Pharmacology and Experimental Therapeutics, 2002
Little is known about cardiac uptake kinetics of idarubicin, including a possible protective role... more Little is known about cardiac uptake kinetics of idarubicin, including a possible protective role of P-glycoprotein (Pgp)mediated transport. This study therefore investigated uptake and negative inotropic action of idarubicin in the single-pass isolated perfused rat heart by using a pharmacokinetic/pharmacodynamic modeling approach. Idarubicin was administered as a 10-min constant infusion of 0.5 mg followed by a 70-min washout period in the absence and presence of the Pgp antagonists verapamil or amiodarone. Outflow concentration and left ventricular developed pressure were measured and the model parameters were estimated by simultaneous nonlinear regression. The results indicate the existence of a saturable, Michaelis-Menten type uptake process into the heart (K m ϭ 3.06 M, V max ϭ 46.0 M/min). Verapamil and amiodarone significantly enhanced the influx rate (V max increased 1.8-fold), suggesting that idarubicin is transported by Pgp directly out of the membrane before it gets into the cell. Verapamil and amiodarone attenuated the negative inotropic action of idarubicin, which was linked to the intracellular concentration of idarubicin.
Journal of Pharmaceutical and Biomedical Analysis, 2011
Daumone, 6-(3,5-dihydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-heptanoic acid is a pheromone secret... more Daumone, 6-(3,5-dihydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-heptanoic acid is a pheromone secreted by Caenorhabditis elegans, and has been known as a pivotal regulator of chemosensory processes in development and ageing. A quantification method using mass spectrometry was developed for the determination of daumone in rat plasma. After simple protein precipitation with acetonitrile including an internal standard, the analytes were chromatographed on a reversed-phase column and detected by liquid chromatography/tandem mass spectrometry with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for validation of bioanalytical methods. This method was applied to measure the plasma daumone concentrations after a single intravenous administration of daumone in rats.
Hepatotoxic and immunotoxic effects of 1-bromohexane (1-BH) and its conjugation with glutathione ... more Hepatotoxic and immunotoxic effects of 1-bromohexane (1-BH) and its conjugation with glutathione (GSH) were investigated in female BALB/c mice. The animals were treated once orally with 1-BH at 500, 1000, and 2000 mg/kg in corn oil for a dose-response study or treated orally with 1-BH at 2000 mg/kg for 6, 12, 24, and 48 hr for a time-course study. Treatment with 1-BH increased serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) dose dependently. The hepatic contents of thiobarbituric acid reactive substances were significantly increased at 2000 mg/kg of 1-BH from 12 to 24 hr after the treatment. Oral 1-BH at 2000 mg/kg significantly suppressed production of splenic intracellular interleukin (IL)-2 in response to concanavalin A. Following treatment with 1-BH, three GSH conjugates such as S-hexyl GSH, S-hexyl cysteine, and hydroxyhexyl mercapturic acid were identified in livers by liquid chromatography-electrospray ionization tandem mass spectrometry. The hepatic contents of GSH were maximally decreased 6 hr after treatment with 1-BH. GSH conjugates were also detected maximally in livers 6 hr after treatment. These results suggest that 1-BH could cause hepatotoxicity and immunotoxicity as well as depletion of GSH content due to the formation of GSH conjugates with 1-BH in female BALB/c mice.
We used a novel chromatographic method to rapidly and simply characterize the pharmacokinetics of... more We used a novel chromatographic method to rapidly and simply characterize the pharmacokinetics of benidipine enantiomers in human plasma. The stereoisomers of benidipine were extracted from plasma using diethylether under alkaline conditions. After evaporating the organic layer, the residue was reconstituted in the mobile phase (methanol:acetic acid:triethylamine, 100:0.01:0.0001, v/v/v). The enantiomers in the extract were separated on a macrocyclic antibiotic (Vancomycin) chiral stationary phase column. The mobile phase was eluted at 1 ml/min and was split by an interface. One-fifth of the eluent was used to quantify both isomers in a tandem mass spectrometer in multiple reactionmonitoring mode. The coefficient of variation of the precision of the assay was less than 8%, the assay accuracy was between 93.4 and 113.3%, and the limit of detection was 0.05 ng/ml for 1 ml of plasma. The method described above was used to measure the concentration of both benidipine enantiomers in plasma from healthy subjects who received a single oral dose of a racemate of 8 mg benidipine. The C max and AUC inf values of (+)-alpha benidipine were higher than those of (−)-alpha benidipine by 1.96-and 1.85-fold, respectively (p < 0.001), whereas, the T max and t 1/2 for each of the benidipine stereoisomers were not significantly different.
We evaluated the herb-drug interaction potential of Galgeun-tang (GGT) extracts, mediated by cyto... more We evaluated the herb-drug interaction potential of Galgeun-tang (GGT) extracts, mediated by cytochrome P450 (CYP) inhibition/induction. Further, the effects of fermentation on the CYP-mediated herb-drug interaction potential of GGT extracts were determined. As measured by LC-ESI/MS/MS, GGT extracts (0-300μg/mL) showed no inhibitory activity toward eight CYP isoforms (1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) in pooled human liver microsomes, suggesting that GGT may have low potential for herb-drug interactions mediated by CYP inhibition. Hepatic CYP expression and activity in rats treated with GGT extracts twice per day for 1week was examined. Among the tested CYP isoforms (1A1, 1A2, 1B1, 2B1, 2C11, 2E1, 3A1, 3A2, and 4A1), CYP1B1 and 4A1 were increased by GGT extracts. Hepatic activities of 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase, but not midazolam hydroxylase were also elevated. These results raise the possibility that GGT extracts may increase the toxicity of environmental toxicants through the elevating CYP-dependent metabolic activation. Interestingly, the increases in CYP1B1 and CYP4A1 levels, and 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase activities were attenuated by fermentation of GGT extract using Lactobacillus plantarum KFRI 402, but not 144. Further studies are needed to identify the CYP regulatory component(s) from GGT and determination its metabolism.
Purpose Talniflumate was designed as a prodrug of niflumic acid, a potent analgesic and anti-infl... more Purpose Talniflumate was designed as a prodrug of niflumic acid, a potent analgesic and anti-inflammatory drug, which is widely prescribed for treating rheumatoid diseases. The prandial effect on talniflumate absorption remains unclear; therefore, this study investigated the effect of food on the systemic exposure to niflumic acid in healthy volunteers. Methods Volunteers received a single 740-mg dose of talniflumate 30 min after consuming a high-fat breakfast, a low-fat breakfast, or no food (fasting condition). Plasma concentrations of both talniflumate and niflumic acid were measured using validated high-performance liquid chromatography coupled to tandem mass spectrometry. Results The maximum concentration of niflumic acid was 224±193 ng/ml at ∼2.7 h in the fasted condition compared with 886±417 ng/ml (p<0.05) at 1.8 h and 1,159±508 ng/ml (p<0.01) at 2.2 h with the low-and high-fat meals, respectively. The mean area under the curve from zero to infinity (AUC inf) values after the low-and high-fat meals were four-and fivefold, respectively, the value while fasting (p<0.05). Conclusions It is strongly recommended that talniflumate be taken after a meal to increase systemic exposure to its active metabolite. Our results suggest a reduction in the daily dosage of talniflumate when taken with food.
Background: Clopidogrel, a potent antiplatelet agent, reduces the risk for thrombotic events in p... more Background: Clopidogrel, a potent antiplatelet agent, reduces the risk for thrombotic events in patients with atherothrombotic diseases. Clopidogrel is marketed primarily as a bisulfate salt. A different salt preparation of clopidogrel, clopidogrel besylate, has been developed and might provide an additional treatment option for patients. Objective: The aim of this study was to compare the pharmacokinetic, pharmacodynamic, and tolerability profiles of clopidogrel besylate with those of clopidogrel bisulfate to determine bioequivalence for the purposes of marketing approval. Methods: A randomized, open-label, 2-period, single-and multiple-dose, comparative crossover study was conducted in healthy Korean male subjects. The subjects received either clopidogrel bisulfate or clopidogrel besylate as a single 300-mg oral loading dose (day 1) followed by a 75-mg/d (once daily) maintenance dose on days 2 to 6. After a 15-day washout period, subjects were administered the alternative salt preparation according to the same protocol. The plasma concentrations of clopidogrel and its primary metabolite (SR26334) were assessed using high-performance liquid chromatography/tandem mass spectrometry after administration of the loading dose. The platelet aggregation response to 10-μmol/L adenosine diphosphate was measured using turbidometric aggregometry during the single-and multiple-dosing periods and at steady state (day 6). Tolerability was monitored using physical examination, including vital sign measurements, and laboratory analysis. Results: Forty-four subjects were enrolled and completed the study (mean [SD] age, 24.3 [2.7] years; weight, 70.0 [8.2] kg). The mean values for C max , T max , and AUC 0-t with clopidogrel (parent drug) of clopidogrel besylate (5.2 ng/mL, 0.9 hour, and 10.1 ng/mL/h, respectively) were similar to those with clopidogrel bisulfate (5.4 ng/mL, 0.9 hour, and 10.3 ng/mL/h). The mean values for C max , AUC 0-t , and AUC 0-∞ with the SR26334 of clopidogrel besylate (10.9 μg/mL, 38.8 μg/mL/h, and 43.0 μg/mL/h, respectively) were not significantly different from those with the SR26334 of clopidogrel bisulfate (11.9 μg/mL, 40.6 μg/mL/h, and 43.8 μg/mL/h). The mean values for maximal antiplatelet effect (E max) and area under the time-effect curve (AUEC) with the 2 clopidogrel salt preparations were as follows: clopidogrel besylate, 58.8 h • % and 4299.1 h • % inhibition, respectively; and clopidogrel bisulfate, 61.7 h • % and 4406.9 h • % inhibition; these differences were not statistically significant. The 90% CIs for the ratios of the log-transformed C max , AUC, E max , and AUEC values were within the predetermined bioequivalence range of 80% to 125%. Three adverse events (6.8%) were reported during the study and included abdominal discomfort (1 subject [2.3%] in the group that received clopidogrel bisulfate), easy fatigability (1 subject [2.3%] immediately before administration of loading dose of clopidogrel besylate), and thrombocy
The purpose of this investigation was to develop a method for measuring the concentration of octy... more The purpose of this investigation was to develop a method for measuring the concentration of octylonium in human plasma. Hydrochloric acid was added to the plasma samples before pretreatment to improve the stability of the octylonium. After liquidliquid extraction with ethylacetate ...
A rapid and sensitive method to assay torasemide in plasma was developed using a simple liquid-li... more A rapid and sensitive method to assay torasemide in plasma was developed using a simple liquid-liquid extraction technique followed by high-performance liquid chromatography. Torasemide and the internal standard furosemide were extracted from 0.5 mL of plasma using ethyl acetate in the presence of 0.1M HCl. The analysis of the extracts was performed on a monolithic silica column with ultraviolet spectrophotometric detection. The calibration curve was linear over the concentration range of 0.05-5 lg mL)1 in plasma. Recoveries were reasonable for routine analyses (>80%); the limit of quantification was 0.05 lg mL)1 with a signal-to-noise ratio of 5. The coefficient of variation of the assay precision was less than 6.1%, and the accuracy exceeded 98%. This method was used to measure the torasemide concentration in plasma from healthy subjects after a single 20-mg oral dose of torasemide. This method provides a very simple, sensitive, and accurate way to determine torasemide concentrations in plasma.
Cefetamet is a potent antibiotic to treat respiratory and urinary tract infections. To improve or... more Cefetamet is a potent antibiotic to treat respiratory and urinary tract infections. To improve oral bioavailability, it is administered as a prodrug, cefetamet pivoxyl hydrolyzed by esterase following absorption. A quantification method using a mass spectrometry was developed for the determination of cefetamet in human plasma. After a protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase C₁₈ column and detected by a tandem mass spectrometer with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This method was used to measure the concentrations of the cefetamet in plasma after a single oral administration of 500 mg cefetamet pivoxyl.
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