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ABSTRACT: Two new phenolics, (3S,4R)-3,7,2',3'-tetrahydroxy-3,4-dihydro-9H-indeno[6,5-c]chromene (caesalpiniaphenol E, 1), and (3R,4S)-3,7-dihydroxy-3-(3'-methoxy-4'-hydroxyphenyl)-4-methoxychroman (caesalpiniaphenol F, 2), together with eleven known compounds (3-13), were isolated from the heartwood of Caesalpinia sappan. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. Their anti-inflammatory activity was evaluated against LPS-induced NO production in macrophage RAW264.7 cells. Among them, compounds 10 and 13 showed strong inhibitory activities toward the LPS-induced NO production in macrophage RAW264.7 cells, with IC(50) values of 12.5 and 8.1μm, respectively. In addition, compounds 10 and 13 inhibited the inductions of iNOS mRNA in dose-dependent manners, indicating that these compounds attenuated the synthesis of these transcripts at the transcriptional level.
Bioorganic & medicinal chemistry letters 10/2012; · 2.65 Impact Factor
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ABSTRACT: This study reports the pharmacokinetics and tissue distribution of a novel histone deacetylase and DNA methyltransferase inhibitor, psammaplin A (PsA), in mice. PsA concentrations were determined by a validated LC-MS/MS assay method (LLOQ 2 ng/mL). Following intravenous injection at a dose of 10 mg/kg in mice, PsA was rapidly eliminated, with the average half-life (t(1/2, λn)) of 9.9 ± 1.4 min and the systemic clearance (CL(s)) of 925.1 ± 570.1 mL/min. The in vitro stability of PsA was determined in different tissue homogenates. The average degradation t(1/2) of PsA in blood, liver, kidney and lung was found relatively short (≤ 12.8 min). Concerning the in vivo tissue distribution characteristics, PsA was found to be highly distributed to lung tissues, with the lung-to-serum partition coefficients (K(p)) ranging from 49.9 to 60.2. In contrast, PsA concentrations in other tissues were either comparable with or less than serum concentrations. The high and specific lung targeting characteristics indicates that PsA has the potential to be developed as a lung cancer treatment agent.
Archives of Pharmacal Research 10/2012; 35(10):1849-54. · 1.59 Impact Factor
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ABSTRACT: Inhalable deoxycholic acid-modified glycol chitosan (DOCA-GC) nanogels containing palmityl acylated exendin-4 (Ex4-C16) were prepared by self-assembly and characterized physicochemically. The lung deposition of DOCA-GC nanogels was monitored using an infrared imaging system, and the hypoglycemia caused by Ex4-C16-loaded DOCA-GC nanogels was evaluated after pulmonary administration in type 2 diabetic db/db mice. The cytotoxicities and lung histologies induced by DOCA-GC nanogels were examined in human lung epithelial cells (A549 and Calu-3) and db/db mice, respectively. Results showed that the DOCA-GC nanogels prepared were spherical and compact and had a diameter of ~220 nm. Although the incorporation of Ex4-C16 (50.9±7.8%) into DOCA-GC nanogels was significantly lower than that of Ex4 (81.4±4.9%), the Ex4-C16 release from DOCA-GC nanogels was greatly delayed vs. Ex4. DOCA-GC nanogels were deposited rapidly after pulmonary administration and remained in the lungs for ~72 h. Furthermore, the hypoglycemic duration of inhaled Ex4-C16 nanogels was much greater than that of Ex4 nanogels in db/db mice. Cytotoxicity results of DOCA-GC nanogels were considered acceptable, and the tissue histologies of mouse lungs administered nanogels did not show any significant difference vs. control lungs. The authors believe that Ex4-C16 DOCA-GC nanogels offer a long-acting inhalation delivery system for treating type 2 diabetes.
Journal of Controlled Release 05/2012; 161(3):728-34. · 5.73 Impact Factor
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ABSTRACT: Doxorubicin-loaded highly porous large PLGA microparticles (Dox PLGA MPs) were prepared using a w/o/w double emulsification method using ammonium bicarbonate effervescent salt. The prepared Dox PLGA MPs were characterized by particle size analysis, scanning electron microscopy, and confocal microscopy. In vitro cytotoxicity to B16F10 melanoma cells and lung deposition in C57BL/6 mice were examined, and finally the anti-tumor efficacy of pulmonary administered Dox PLGA MPs was evaluated in a mouse model of B16F10 melanoma metastasis. Results showed that Dox PLGA MPs were highly porous, had high encapsulation efficiency, and good aerosolization characteristics. Doxorubicin was gradually released from Dox PLGA MPs over 2 weeks, and after pulmonary administration, Dox PLGA MPs were deposited in lungs and remained in situ for up to 14 days. Furthermore, exposure to Dox PLGA MPs killed B16F10 cells in vitro within 24 h. In particular, tumors in B16F10-implanted mice treated with Dox PLGA MPs were remarkably smaller in terms of mass and number than those in non-treated B16F10-implanted mice. We believe that doxorubicin-loaded highly porous large PLGA microparticles have great potential as a long-term inhalation agent for the treatment of lung cancer.
Biomaterials 05/2012; 33(22):5574-83. · 7.40 Impact Factor
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ABSTRACT: A simple and sensitive liquid chromatographic assay with fluorescence detection assay was developed for the determination
of zearalenone levels in rat serum. The assay utilized a single liquid–liquid extraction with t-butyl methyl ether and isocratic elution using a mobile phase consisting of acetonitrile and 0.1% triethylamine in distilled
water (pH=6) (50:50, v/v). Linearity was observed over a concentration range from 10 to 1,000ngmL−1 (r=0.9995), with the limit of quantification at 10ngmL−1 with 100μL of rat serum. The validated assay was applied to a pharmacokinetic study in rats.
Chromatographia 04/2012; 69(3):295-299. · 1.20 Impact Factor
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ABSTRACT: PurposeThis study was conducted to examine the absorption and tissue distribution characteristics of paclitaxel-loaded DHP 107, a
Cremophor EL-free, mucoadhesive lipid oral dosage form.
MethodsDHP 107 was orally administered to mice at 10, 20 and 40mg/kg doses. For comparison purposes, Taxol was i.v. injected at
5, 10 and 20mg/kg doses. Drug levels were determined in plasma and tissues by validated HPLC assays. The absolute bioavailability
and the relative distribution to various tissues were calculated as a function of dose.
ResultsThe dose-normalized plasma AUCDHP 107/AUCTaxol ratios calculated at comparable AUC values ranged from 14.6 to 29.0%. In contrast, relative tissue distribution ratios calculated
as the dose-normalized AUCDHP 107/AUCTaxol were as high as 342.0, 139.0, 112.9 and 108.2% for stomach, small intestine, large intestine and ovary, respectively.
ConclusionsOral administration of DHP 107 provided a substantial systemic absorption of paclitaxel. Furthermore, the relative distribution
ratios of DHP 107 at doses of 20 and 40mg/kg were higher for stomach, small intestine, large intestine, and ovary than the
systemic bioavailability, providing a basis for therapeutic advantages.
Cancer Chemotherapy and Pharmacology 04/2012; 64(1):87-94. · 2.83 Impact Factor
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ABSTRACT: Glimepiride, a second-generation sulfonylurea, is a glucose-lowering agent widely used to treat diabetes mellitus. It is converted into metabolite M1 by CYP2C9, and M1 is then transformed into the carboxyl derivative M2 by cytosolic enzymes. In this study, we introduce a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for determining glimepiride, M1, and M2 in human plasma. After simple protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase CN column with a mobile phase of 10 mM ammonium acetate aqueous solution and acetonitrile (1:1, v/v). 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 glimepiride, M1, and M2 in plasma after a single oral 2-mg dose of glimepiride in volunteers.
Archives of Pharmacal Research 12/2011; 34(12):2073-8. · 1.59 Impact Factor
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ABSTRACT: This study describes the development of a rapid and sensitive high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) assay for the quantification of [6]-gingerol in mouse plasma and application to a pharmacokinetic study after dose ranging in mice. The assay involved a protein precipitation step with acetonitrile and an isocratic elution using a mobile phase consisting of acetonitrile and water containing 0.1% formic acid (80:20 v/v). The multiple reaction monitoring was based on the transition of m/z = 277.2 → 177.1 for [6]-gingerol and 294.2 → 137.1 for nonivamide (internal standard). The assay was validated to demonstrate the specificity, linearity, recovery, accuracy, precision and stability. The calibration curves were linear over the wide concentration range of 10-10,000 ng/mL (r ≥ 0.9988). The lower limit of quantification was 10 ng/mL using a small volume of mouse plasma (20 μL). The method was successfully applied to a pharmacokinetic study in mice after intravenous injection of [6]-gingerol at 1.5, 3 and 6 mg/kg doses. The pharmacokinetics of [6]-gingerol were linear over the dose range studied as demonstrated by the linear increase in area under the concentration-time curve (AUC(inf)) with no significant change in the systemic clearance (Cl(s)), volume of distribution (V(ss)) and elimination half-life (t(1/2)) as a function of dose.
Biomedical Chromatography 09/2011; 26(5):660-5. · 1.97 Impact Factor
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Mi Jeong Kang,
Hyun Woo Ha,
Hyung Gyun Kim,
Dae Hun Lee,
Min Jeong Kong,
Young Tae Ahn,
Dong Hyun Kim, Beom Soo Shin,
Wonku Kang,
Hye Gwang Jeong,
Tae Cheon Jeong
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ABSTRACT: A possible role of metabolism by intestinal bacteria in arbutin-induced toxicity was investigated in mammalian cell cultures. Following an incubation of arbutin with intestinal bacteria, either Bifidobacterium longum HY81 or Bifidobacterium adolescentis, for 24 h, its aglycone hydroquinone could be produced and detected in the bacterial culture media. The bacterial growth was not affected up to 10 mM arbutin in the culture medium. When the toxicity of bacteria cultured medium with arbutin was tested in the HepG2 cell lines, the medium with arbutin was more toxic than either parent arbutin only or bacteria cultured medium without arbutin, indicating that metabolic activation might be required in arbutin-induced toxicity. In addition, bacteria cultured medium with arbutin could suppress LPS and ConA mitogenicity in splenocyte cultures prepared from normal mice. The results indicate that the present toxicity testing system might be applied for assessing the possible role of metabolism by intestinal bacteria in certain chemical-induced toxicity in mammalian cell cultures.
Archives of Pharmacal Research 04/2011; 34(4):687-93. · 1.59 Impact Factor
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ABSTRACT: Fimasartan, 2-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H tetrazol -5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one (BR-A-657), is a novel angiotensin II receptor blocker exhibiting potent and selective AT1 receptor blocking activity. This study reports the liquid chromatography–tandem mass spectrometry assay for the simultaneous determination of fimasartan and its active metabolite, BR-A-557, in rat plasma. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification, accuracy, precision and stability. The multiple reaction monitoring was based on the transition of m/z 502.1 → 207.1 for fimasartan, 486.2 → 207.1 for BR-A-557 and 526.1 → 207.1 for BR-A-563 (internal standard). The assay utilized a simple precipitation procedure with acetonitrile and isocratic elution. The LLOQ was 0.2 ng/mL for fimasartan and BR-A-557 using 50 μL plasma samples. The assay was linear over a concentration range from 0.2 to 500 ng/mL for fimasartan and BR-A-557, with correlation coefficients >0.9995. The intra- and inter-day assay accuracies were 93.6–108.0 and 90.8–101.4% for fimasartan and 102.2–107.1 and 99.6–103.3% for BR-A-557, respectively. The intra- and inter-day precision were 2.4–4.4 and 3.0–13.4% for fimasartan and 3.1–5.2 and 2.8–9.8% for BR-A-557, respectively. The developed assay may be used to study the metabolism and mechanistic pharmacokinetics of fimasartan in future studies. Copyright © 2011 John Wiley & Sons, Ltd.
Biomedical Chromatography 01/2011; 25(11):1208 - 1214. · 1.97 Impact Factor
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ABSTRACT: This study assessed the population pharmacokinetics and metabolic conversion of a novel histone deacetylase (HDAC) inhibitor, SD-2007, into its active metabolite, apicidin, in rats.
SD-2007 was given to rats by intravenous injection (4 mg/kg) and oral administration (40 mg/kg). Serum concentrations of SD-2007 and apicidin were determined by LC-MS/MS. All concentrations were analyzed using a population pharmacokinetic model with 9 compartments in S-ADAPT.
The area under the curve for apicidin was 96 ± 16 mg·h/ml after 4 mg/kg administered intravenously and 2,455 ± 1,211 mg·h/ml after 40 mg/kg given orally. The population pharmacokinetic model described all profiles well. After oral administration of SD-2007, the median absolute bioavailability of SD-2007 was 6.67% (range 3.83-9.89) and the median apparent bioavailability was 22.3% (range 15.7-35.8) for apicidin, whereas only a median of 8.85% (range 7.57-9.34) of an intravenous SD-2007 dose was converted to apicidin.
Oral SD-2007 displayed a substantial presystemic metabolism to active apicidin. The high serum concentrations of apicidin after oral administration of SD-2007 may cause significant HDAC inhibition.
Chemotherapy 01/2011; 57(3):259-67. · 1.82 Impact Factor
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ABSTRACT: The objectives of this study were to develop physiologically based models for the pharmacokinetics (PK) and organ distribution of apicidin in rats and mice and to predict human PK in blood and organs.
The PK of apicidin was characterized in rats and mice after i.v. bolus injection, and distribution to various tissues was determined in rats following i.v. infusions at steady state. The developed models were prospectively validated within rat and within mouse and by scaling from rat to mouse using data after multiple i.v. injections. Human PK was predicted by the physiologically based modeling using intrinsic clearance data for humans from in vitro experiments.
The Cl(s) predicted for human (9.8 ml/min/kg) was lower than those found in mice (116.9 ml/min/kg) and rats (61.6 ml/min/kg), and the V(ss) predicted for human (1.9 l/kg) was less than in mice (2.0 l/kg) and rats (2.5 l/kg). Consequently, the predicted t (1/2) was longer in human (2.3 h) than in mice and rats (0.4 and 0.9 h, respectively). The highest concentrations of apicidin were predicted in liver followed by adipose tissue, kidney, lung, spleen, heart, arterial blood, venous blood, small intestine, stomach, muscle, testis, and brain.
The developed models adequately described the PK of apicidin in rats and mice and were applied to predict human PK. These models may be useful in predicting human blood and tissue concentrations of apicidin under different exposure conditions.
Cancer Chemotherapy and Pharmacology 11/2010; 68(2):465-75. · 2.83 Impact Factor
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ABSTRACT: Five flavonoids, myricetin-3'-methylether 3-O-β-D: -galactopyranoside (1), myricetin-3',5'-dimethylether 3-O-β-D: -galactopyranoside (2), quercetin (3), kaempferol (4), and tamarixetin (5) were isolated from the buds of Cleistocalyx operculatus (Myrtaceae). The chemical structures of these compounds were determined on the basis of spectroscopic analyses, including 2D NMR. Their anti-Alzheimer effects were evaluated via acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity assays. All five compounds 1-5 showed potential inhibitory activities against AChE with IC(50) values of 19.9, 37.8, 25.9, 30.4 and 22.3 μM, respectively, while compounds 1, 3, 4 and 5 also possessed BChE inhibitory activity with IC(50) values of 152.5, 177.8, 62.5, and 160.6 μM, respectively.
Archives of Pharmacal Research 10/2010; 33(10):1665-70. · 1.59 Impact Factor
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03/2010; , ISBN: 9780470571224
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ABSTRACT: The objective of this study was to predict the exposure to bisphenol A (BPA) after oral intake in human blood and tissues using physiologically based pharmacokinetic (PBPK) modeling. A refined PBPK model was developed taking into account of glucuronidation, biliary excretion, and slow absorption of BPA in order to describe the second peak of BPA observed following oral intake. This developed model adequately described the second peak and BPA concentrations in blood and various tissues in rats after oral administration. A prospective validation study in rats additionally supported the proposed model. For extrapolation to humans, a daily oral BPA dose of 0.237 mg/70 kg/d or 0.0034 mg/kg/d was predicted to achieve an average steady-state blood concentration of 0.0055 ng/ml (median blood BPA concentration in Korean pregnant women). This dose was lower than the reference dose (RfD, 0.016 mg/kg/d) and the tolerable daily intake established by the European Commission (10 μg/kg/d). Data indicate that enterohepatic recirculation may be toxicologically important as this pathway may increase exposure and terminal half-life of BPA in humans.
Journal of Toxicology and Environmental Health Part A 01/2010; 73(21-22):1586-98. · 1.83 Impact Factor
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Kyoungjin Bae,
Kyeumhan Noh,
Kiyoung Jang,
Sohee Kim,
Chul Soon Yong,
Han-Gon Choi,
Jong Seong Kang,
Jianbo Chen,
Eunsook Ma,
Manhyung Lee, Beom Soo Shin,
Kwang-Il Kwon,
Wonku Kang
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ABSTRACT: Sibutramine, a monoamine reuptake inhibitor, is used as a racemate, for the treatment of obesity. It is converted in vivo mainly to two desmethyl active metabolites, mono-desmethylsibutramine (MDS) and di-desmethylsibutramine (DDS). In the present study, we introduced a rapid and simple chromatographic method for separating the R(+)- and S(-)-isomers of sibutramine, MDS, and DDS, respectively. The stereoisomers of the three compounds were extracted from rat plasma using diethyl ether and n-hexane under alkaline conditions. After evaporating the organic layer, the residue was reconstituted in the mobile phase (10 mM ammonium acetate buffer adjusted to pH 4.03 with acetic acid:acetonitrile, 94:6, v/v). The enantiomers in the extract were separated on a Chiral-AGP stationary-phase column and were quantified in a tandem mass spectrometry. 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 enantiomers of sibutramine, MDS, and DDS in plasma after a single oral dose of 10 mg/kg racemic sibutramine in rats.
Journal of pharmaceutical and biomedical analysis 10/2009; 50(2):267-70. · 2.45 Impact Factor
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ABSTRACT: A simple, specific and sensitive derivatization with monobromobimane (mBrB) and the corresponding HPLC-fluorescence quantitation method for the analysis of bucillamine in human plasma was developed and validated. The analytical procedure involves a simple protein precipitation, pre-column fluorescence derivatization, and separation by reversed-phase high performance liquid chromatography (RP-HPLC). The calibration curve showed good linearity over a wide concentration range (50 ng/mL to 10 microg/mL) in human plasma (r(2)=0.9998). The lower limit of quantitation (LLOQ) was 50 ng/mL. The average precision and accuracy at LLOQ were within 6.3% and 107.6%, respectively. This method was successfully applied to a pharmacokinetic study after oral administration of a dose (300 mg) of bucillamine to 20 healthy Korean volunteers.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 07/2009; 877(22):2130-4. · 2.78 Impact Factor
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ABSTRACT: Zearalenone, a mycotoxin biosynthesized by various Fusarium fungi, is widely found as a contaminant in grains and animal feeds. This study describes a rapid and sensitive LC/MS/MS assay method for the quantification of zearalenone in rat serum. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification (LLOQ), accuracy and precision. The multiple reaction monitoring was based on the transition of m/z 317.0 --> 130.9 for zearalenone and 319.0 --> 204.8 for zearalanone (internal standard). The assay utilized a single liquid-liquid extraction with t-butyl methyl ether and isocratic elution, and the LLOQ was 0.5 ng/mL using 0.1 mL rat serum. The assay was linear over a concentration range from 0.5 to 200 ng/mL, with correlation coefficients >0.9996. The mean intra- and inter-day assay accuracy was 101.2-112.9 and 96.3-108.0%, respectively. The mean intra- and inter-day precision was between 1.3-7.6 and 3.6-10.6%, respectively. The developed assay was applied to a pharmacokinetic study after a bolus intravenous injection of zearalenone in rats.
Biomedical Chromatography 04/2009; 23(9):1014-21. · 1.97 Impact Factor
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ABSTRACT: This study was conducted to predict the pharmacokinetics of oleanolic acid in humans based on animal data by allometry and several species-invariant time methods. Oleanolic acid was injected intravenously to mice, rats, rabbit and dogs (dose 1 mg/kg). The serum concentration-time profiles of oleanolic acid were best described by bi-exponential equation in all animal species. The average Cl, V ( ss ) and t ( 1/2 ) were 0.065 L/h, 0.019 L and 28.7 min in mice, 0.47 +/- 0.06 L/h, 0.117 +/- 0.029 L and 29.7 +/- 12.2 min in rats, 2.77 +/- 0.88 L/h, 1.83 +/- 0.60 L and 84.4 +/- 16.9 min in rabbits and 14.0 +/- 0.7 L/h, 9.2 +/- 10.1 L and 54.5 +/- 57.2 min in dogs, respectively. Based on animal data, human pharmacokinetic parameters of Cl, V ( ss ) and t (1/2) were predicted by simple allometry. In addition, actual concentration-time profiles obtained from animals were transformed to human profiles by species-invariant times of kallynochron, apolysichron and dienetichron. The predicted human pharmacokinetic parameters of Cl, V ( ss ) and t (1/2) by using simple allometry and species-invariant time transformation method ranged from 48.3-97.2 L/h, 49.1-92.9 L and 45.6-187.2 min, respectively. Those predicted parameters of oleanolic acid may be useful in designing dosing schedules of oleanolic acid in future clinical studies.
Archives of Pharmacal Research 03/2009; 32(2):251-7. · 1.59 Impact Factor
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ABSTRACT: A sensitive high performance liquid chromatography method (HPLC) has been developed for the quantification of doxorubicin in mouse plasma and tissues. Samples of serum or tissue homogenates, 20 microl, were analyzed following a single step protein precipitation using perchloric acid (35%, v/v). Doxorubicin was separated from the internal standard, daunorubicin, on a Zorbax 300SB C(18) column at 35 degrees C. Mobile phase was comprised of acetonitrile and water (25:75) containing 0.1% triethylamine, and was adjusted to pH 3 with phosphoric acid. Peaks eluting from the column were detected with a fluorescence detector with excitation and emission wavelengths of 480 and 560 nm, respectively. Standard curves were linear in the range 5-1000 ng/ml, and correlation coefficients were typically greater than 0.999. Intra-assay recoveries ranged from 94.7 to 99.9%, and inter-assay recoveries were in the range of 95.2-101%. The associated coefficient of variation (CV) was less than 10% in all cases. The method was successfully applied to investigate doxorubicin plasma pharmacokinetics and tissue distribution in athymic Fox(nu) mice.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 03/2009; 877(8-9):837-41. · 2.78 Impact Factor
