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Emerging evidence has suggested that bexarotene, a nearly 20-year-old skin cancer drug, may be a potential drug candidate to treat Alzheimer's disease (AD) and other neurodegenerative disorders. As described in this study, a highly sensitive and rapid method, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine bexarotene in mouse plasma and brain tissue, was established and validated for the first time. Single-step protein precipitation utilizing methanol solution (containing 0.05 % acetic acid) as precipitation agent was employed to prepare the samples of plasma and brain tissue. Chromatographic separation in gradient elution mode was conducted via an Agilent ZORBAX SB-C18 column (50 mm × 4.6 mm, 5 µm) employing methanol-ammonium acetate buffer (5 mM, pH adjusted to 4.6 with acetic acid) as mobile phase which flowed at 0.45 mL/min. The total run time was 6 min for each sample. Detection through mass spectrometric technique was operated by selected reaction monitoring (SRM) in negative electrospray ionization mode. The method was linear within the range of 10.0-15000 ng/mL for plasma and 10.0-600 ng/mL for brain tissue homogenate with the lower limit of quantification of 10.0 ng/ml. The plasma or tissue homogenate was only required 20 μL. The intra- and inter-day precision were less than 13.8 %, and the RE was between -7.4 % and 3.4 %. The method was applied to investigate the plasma pharmacokinetics and brain distribution of bexarotene in mice after being intragastrically administered with bexarotene at the dosage of 100 mg/kg. The results showed that both brain and plasma concentrations of bexarotene peaked at 1.0 h. Bexarotene was rapidly eliminated with a half-life of 2.0 h., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In this study, a rapid and reliable high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of ambroxol in human plasma was developed and validated using palmatine as an internal standard (IS). Ambroxol and IS were extracted from 200 μL of human plasma via a simple protein precipitation preparation. Chromatographic separation was achieved on a Platisil C18 column (150 × 4.6 mm, 5 μm) using methanol-0.01% formic acid (70:30, v/v) as the mobile phase at a flow rate of 0.6 mL/min under an isocratic condition. The MS acquisition m/z 379 → 264 for ambroxol and 352 → 336 for IS was performed by atmospheric-pressure chemical ionization (APCI) mass spectrometry in selected reaction monitoring mode. The calibration curve for ambroxol was linear over the concentration range of 2.500 - 180.0 ng/mL. The matrix effects of ambroxol ranged from 104.6 to 112.7%. This fully validated method was successfully applied to a pharmacokinetic study of ambroxol in humans after oral administration of ambroxol at a single dose of 75 mg.

A rapid and sensitive LC-MS/MS method was developed for the determination of linarin in small-volume rat plasma and tissue sample. Sample preparation was employed by the combination of protein precipitation (PPT) and liquid-liquid extraction (LLE) to allow measurement over a 5-order-of-magnitude concentration range. Fast chromatographic separation was achieved on a Hypersil Gold column (100 × 2.1 mm i.d., 5 µm). Mass spectrometric detection was achieved using a triple-quadrupole mass spectrometer equipped with an electrospray ionization interface operating in positive ionization mode. Quantification was performed using selected reaction monitoring of precursor-product ion transitions at m/z 593 → 285 for linarin and m/z 447 → 271 for baicalin (internal standard). The total run time was only 2.8 min per sample. The calibration curves were linear over the concentration range of 0.4-200 µg/mL for PPT and 0.001-1.0 µg/mL for LLE. A lower limit of quantification of 1.0 ng/mL was achieved using only 20 μL of plasma or tissue homogenate. The intra- and inter-day precisions in all samples were ≤14.7%, while the accuracy was within ±5.2% of nominal values. The validated method has been successfully applied to pharmacokinetic and tissue distribution study of linarin., (Copyright © 2015 John Wiley & Sons, Ltd.)

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) has been widely used as a traditional medicine and was shown to possess a multitude of health-promoting properties in pre-clinical studies, but its bioavailability was low due to the extensive glucuronidation in liver and intestine, hindering the development of emodin as a feasible chemopreventive agent. In this study, piperine, as a bioenhancer, was used to enhance the bioavailability of emodin by inhibiting its glucuronidation. The pharmacokinetic profiles of emodin after oral administration of emodin (20mg/kg) alone and in combination with piperine (20mg/kg) to rats were investigated via a validated LC/MS/MS method. As the in vivo pharmacokinetic studies had indicated, the AUC and Cmax of emodin were increased significantly after piperine treatment, and the glucuronidation of emodin was markedly inhibited. Our study demonstrated that piperine significantly improved the in vivo bioavailability of emodin and the influence of piperine on the pharmacokinetics of emodin may be attributed to the inhibition of glucuronidation of emodin. Further research is needed to investigate the detailed mechanism of improved bioavailability of emodin via its combination with piperine., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of febuxostat and its three active metabolites in human plasma was developed using a ZORBAX SB-C18 column (50 mm × 4.6 mm, 5 μm) and an optimized gradient mobile phase consisting of acetonitrile, water and formic acid. Plasma samples were spiked with the internal standard losartan and then pre-treated using one-step protein precipitation with methanol. Mass spectrometric detection was performed by selective reaction monitoring mode via electrospray ionization source operating in positive ionization mode. The method exhibited good linearity over the concentration range of 10-20,000 ng/mL for febuxostat, 1.0-270 ng/mL for 67M-1 and 67M-2, and 0.8-250 ng/mL for 67 M-4, respectively. The intra- and inter-day precisions were less than 14.7% and the accuracy ranged from -4.3% to 5.1%. The method was successfully applied to a clinical pharmacokinetic study of febuxostat in humans after oral administration of a single dose of febuxostat at 40, 80 and 120 mg., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A simple, specific and sensitive LC-MS/MS method was developed and validated for the determination of mesalazine in beagle dog plasma. The plasma samples were prepared by protein precipitation, then the separation of the analyte was achieved on a Waters Spherisorb C6 column (150 × 4.6 mm, 5 µm) with a mobile phase consisting of 0.2% formic acid in water-methanol (20:80, v/v). The flow rate was set at 1.0 mL/min with a split ratio of 3:2. Mass spectrometric detection was achieved by a triple-quadrupole mass spectrometer equipped with an electrospray source interface in positive ionization mode. Quantitation was performed using selected reaction monitoring of precursor-product ion transitions at m/z 154 → m/z 108 for mesalazine and m/z 285 → m/z 193 for diazepam (internal standard). The linear calibration curve of mesalazine was obtained over the concentration range 50-30,000 ng/mL. The matrix effect of mesalazine was within ±9.8%. The intra- and inter-day precisions were <7.9% and the accuracy (relative error) was within ±3.5%. The validated method was successfully applied to investigate the pharmacokinetics of mesalazine in healthy beagle dogs after rectal administration of mesalazine suppository., (Copyright © 2014 John Wiley & Sons, Ltd.)

A selective and sensitive LC-MS/MS method was developed and validated for simultaneous determination of three glucuronide conjugates of scutellarein in rat plasma. Plasma samples were pretreated by protein precipitation with acetonitrile. The analytes (scutellarin, scutellarein-6,7-di-O-β-d-glucuronide and scutellarein-6-O-β-d-glucuronide), together with internal standard (IS, baicalin) were separated on a Diamonsil C18 column (150 mm × 4.6 mm, 5 μm) with an isocratic mobile phase consisting of methanol-water-formic acid (55:45:0.2, v/v/v). Mass spectrometric detection was performed by selected reaction monitoring (SRM) mode via electrospray ionization source operating in negative ionization mode. The method was linear for all the analytes over the investigated concentration ranges with correlation coefficients greater than 0.9954. The intra- and inter-day precisions were less than 9.1% and the relative error was between -1.7% and 4.2%. The extraction recoveries of the analytes and IS from rat plasma were over 63%. The validated method has been successfully applied to a pharmacokinetic study of breviscapine in rats after intragastric administration at a dose of 20mg/kg. The pharmacokinetic results would be helpful to better understand the pharmacological actions of breviscapine., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed, using testosterone-d3 as a surrogate analyte, for the simultaneous quantification of goserelin and testosterone in rat plasma. According to this method, the pharmacokinetic and pharmacodynamic data were obtained from a single plasma sample aliquot. The method involved the addition of alarelin as an internal standard (IS) for goserelin and testosterone-(13)C3 for testosterone or testosterone-d3. The conditions for the separation of these two compounds were achieved on a ZORBAX Eclipse Plus C18 column (Agilent, 2.1 × 50 mm, 1.8 μm, Stockport, UK) in a single chromatographic run at a flow rate of 400 μL/min. In order to minimize interferences of complex matrix, the extraction of plasma consisted of a protein precipitation step using methanol, followed by purification using an Oasis(®) HLB solid-phase extraction column. The method was validated in the concentration range of 0.01-30.0 ng/mL for goserelin and 0.05-30.0 ng/mL for testosterone-d3, respectively. The within- and between-run precisions were 1.7-9.2% and 2.1-6.9%, respectively. The within- and between-run accuracies were -1.8 to 5.3% and -4.9 to 4.0%, respectively. This accurate and highly specific assay provides a useful method to evaluate the pharmacokinetics and pharmacodynamics of goserelin in rats., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The ex vivo instability of bilobalide containing three γ-lactone rings has been paid less attention by researchers who developed bioanalytical methods for bilobalide. In the present study, a sensitive LC-MS/MS method for the determination of bilobalide in rat plasma was developed with special consideration of ex vivo bilobalide stability. Several important factors affecting the stability of bilobalide in sampling and handling procedures were investigated. To prevent the ex vivo degradation of bilobalide, EDTA instead of heparin was used as an anticoagulant as well as an esterase inhibitor for blood collection and the separation of plasma was performed at 4 °C. 20 μL of plasma sample was acidified with 0.1 M hydrochloric acid, and then extracted with ethyl ether-methylene chloride (2:1, v/v). The extract was chromatographed on a Thermo Hypersil GOLD (100 mm × 2.1 mm, 5 μm) column using acetonitrile-10mM ammonium acetate-formic acid (90:10:0.4, v/v/v) as the mobile phase. The analyte and the internal standard (ginkgolide B) were detected by selected reaction monitoring mode via negative electrospray ionization. The method was fully validated and proved to be linear over a concentration range of 5.0-5000 ng/mL. The intra- and inter-day precisions were less than 5.2% and the accuracy was within 92.5-101%. The extraction recoveries ranged from 80.7% to 86.7%. The proposed method was successfully applied to a preclinical pharmacokinetic study of bilobalide in rats after intragastric administration of a single dose of bilobalide at 7, 14 and 28 mg/kg., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Triptorelin, a gonadotropin-releasing hormone agonist, has been used in the treatment of hormone-responsive prostate cancer by inducing testosterone suppression. Research on the relationship between the time courses of triptorelin and testosterone is very important, but accurate quantification of triptorelin and testosterone simultaneously in biological specimens is a challenging analytical problem. In the present study, a rapid, sensitive, and selective method for simultaneous determination of triptorelin and testosterone in rat plasma by solid-phase extraction and liquid chromatography-tandem mass spectrometry was developed using a ZORBAX RRHD Eclipse Plus C8 column (2.1 × 50 mm, 1.8 μm) with a 0.05% propionic acid/methanol gradient. In view of the polarity difference between the two analytes, two internal standards, i.e., leuprolide and testosterone-(13)C3, were used for individual quantitation of triptorelin and testosterone. Endogenous testosterone was determined by reference to a calibration curve prepared using testosterone-D3 as a surrogate analyte. The method exhibits excellent linearity over three orders of magnitude for each analyte. The lower limit of quantification was 0.01 ng/mL for triptorelin and 0.05 ng/mL for testosterone, with consumption of 100 μL of plasma. The method was successfully applied to characterize the pharmacokinetics and pharmacodynamics of slow-release 28-day form triptorelin acetate biodegradable microspheres in rats after intramuscular injections of three consecutive doses of 0.6 mg/kg per 28 days. The results revealed that the pharmacokinetic profile of triptorelin produced an initial flare-up in testosterone levels, rapid castration within 5 days after injection, and long-term castration until the next dose.

Chelidonium majus L. is one of the most important medicinal plants of the family Papaveraceae. Its pharmacological effects have been primarily attributed to the presence of a number of alkaloids. In the present study, a sensitive and selective liquid chromatography-tandem mass spectrometry method for simultaneous determination of five isoquinoline alkaloids from Chelidonium majus L. was developed and validated. The analytes (protopine, chelidonine, coptisine, sanguinarine and chelerythrine), together with the internal standard (palmatine), were extracted from acidified rat plasma with ethyl acetate-dichloromethane (4:1, v/v). Chromatographic separation was carried out on a Diamonsil C(18) column with an isocratic mobile phase consisting of acetonitrile and water (adjusted to pH 2.3 with formic acid) (30:70, v/v) at a flow rate of 0.4 ml/min. Mass spectrometric detection was performed by selected reaction monitoring mode via electrospray ionization source operating in positive ionization mode. The assay exhibited good linearity (r ≥ 0.9933) for all the analytes. The lower limits of quantification were 0.197-1.27 ng/ml using only 50 µl of plasma sample. The intra- and inter-day precisions were less than 11.9%, and the accuracy was between -6.3% and 9.3%. The method was successfully applied to the pharmacokinetic study of the five alkaloids in rats after intragastric administration of Chelidonium majus L. extract., (Copyright © 2013 John Wiley & Sons, Ltd.)

WJ-38 is an aldose reductase inhibitor that is being developed for the treatment of diabetic complications. The present paper describes a sensitive and specific liquid chromatography-tandem mass spectrometry method for the determination of WJ-38 in rat plasma. Partial denaturation of plasma proteins with methanol followed by liquid-liquid extraction using ethyl acetate was used to extract strongly protein-bound WJ-38 from rat plasma. Chromatographic separation was performed on an Inertsil ODS-3 column with an isocratic mobile phase consisting of acetonitrile, water and formic acid (75:25:0.125, v/v/v). Mass spectrometric detection was achieved by a triple-quadrupole mass spectrometer equipped with an ESI interface operating in positive ionization mode. Quantitation was performed using selected reaction monitoring of precursor-product ion transitions at m/z 392→246 for WJ-38 and m/z 446→321 for glipizide (internal standard). A linear calibration curve was obtained over the concentration range of 10.0-10,000 ng/mL for WJ-38 in rat plasma. The intra- and inter-day precisions were less than 13.6% and the accuracy was within ± 5.3%. The extraction recovery of WJ-38 from rat plasma was over 66.0%. The validated method has been successfully applied to a pharmacokinetic study in rats after intragastrical administration of WJ-38., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Some side effects of copper intrauterine devices (Cu-IUDs) including increased uterine bleeding, pelvic infections and pain have been reported. The presence of indomethacin in such devices was found to be effective in relieving the symptoms. The aim of this study was to develop and validate a rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for measuring plasma and uterine tissue levels of indomethacin in rabbits after insertion of indomethacin-medicated Cu-IUDs., Study Design: Indomethacin was extracted from rabbit plasma and uterine tissue by a simple protein precipitation using acetonitrile. Chromatographic separation was carried out on a Diamonsil C(18) column (150×4.6 mm ID, 5 μm) with an isocratic mobile phase consisting of methanol, acetonitrile, water and formic acid (45:45:10:0.5, v/v/v/v). Mass spectrometric detection was achieved by a triple-quadrupole mass spectrometer equipped with an atmospheric pressure chemical ionization interface operating in positive ionization mode. Quantitation was performed using selective reaction monitoring mode. The LC-MS/MS method was validated with respect to selectivity, linearity, precision, accuracy, extraction recovery and stability, and then applied to the in vivo studies of indomethacin in rabbits treated with indomethacin-medicated Cu-IUDs., Results: The linear calibration curves of indomethacin in plasma and uterine tissue were obtained over the concentration range of 2.0-400 ng/mL and 4.0-800 ng/mL, respectively. The intra- and interday precision was less than 9.5%, and the relative error was within ±5.3%. After insertion of indomethacin-medicated Cu-IUDs in rabbits, indomethacin was rapidly absorbed, and peak plasma levels were reached in approximately 1 h. A multiphasic elimination pattern was observed, which was a rapid decline in plasma concentration during the first 100 h followed by a very slow clearance phase. The uterine indomethacin levels were significantly higher than simultaneous plasma levels., Conclusions: The developed method proved to be rapid and sensitive, and was successfully applied to investigate the absorption and uterine distribution of indomethacin in rabbits after insertion of indomethacin-medicated Cu-IUDs., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The lack of authentic standards limits the quantitative analysis of herbal drugs in biological samples. This present work demonstrated a practicable assay of herbs and their metabolites independent of the availability of authentic standards. A liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method for the qualitative and quantitative determination of the metabolites after oral administration of Evodiae fructus and Zuojinwan preparation in rat urine has been developed. Urine samples extracted with a protein precipitation procedure were separated on a C(18) column using a mixture of water (containing 0.1% formic acid) and acetonitrile (30:70, v/v) as mobile phase. The detection was performed by MS with electrospray ionization interface in positive selected reaction monitoring (SRM) mode. One urine sample after administration was selected as 'standard'. The method validation was carried out according to a conventional method that was calibrated by authentic standards. The fully validated method was applied to the pharmacokinetic study of the metabolites in rat urine. The results could provide evidence to explain the combination of Coptidis rhizoma and Evodiae fructus in terms of elimination.

A selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of antrodin B and antrodin C in rat plasma. Both target compounds, together with the internal standard (diazepam), were extracted from rat plasma samples by liquid-liquid extraction with ethyl acetate. Chromatographic separation was carried out on an Agilent XDB-C(8) column with an isocratic mobile phase consisting of acetonitrile and water (70:30, V/V) at a flow rate of 0.5 mL/min. The mass spectrometric detection was performed by selected reaction monitoring (SRM) mode via atmospheric pressure chemical ionization (APCI) source operating in positive ionization mode. The assay exhibited a linear dynamic range of 47.6-4760 ng/mL for antrodin B and 56.6-5660 ng/mL for antrodin C. The intra- and inter-day precision was less than 5.3% and the accuracy was less than 2.7% for both analytes. The validated method has been applied to the pharmacokinetic study of antrodin B and antrodin C in rats following oral administration of Antrodia camphorata extract., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Abstract: The present paper describes a novel, sensitive and selective liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the simultaneous analysis of ganoderic acids C2, B, A, H, D in Ganoderma lucidum and its related species. Ganoderma samples were prepared using simple ultrasonic extraction. Chromatographic separation was carried out on an Agilent Zorbax XDB C18 column (250mm×4.6mm i.d., 5μm) with an isocratic mobile phase consisting of acetonitrile, water and formic acid (42:58:0.5, v/v/v). Mass spectrometric detection was achieved by a triple-quadrupole mass spectrometer equipped with an atmospheric pressure chemical ionization (APCI) interface operating in negative and positive ionization mode via a single within-run polarity switching. Quantitation of five ganoderic acids was performed using selective reaction monitoring (SRM) mode. The intra- and inter-day precision was less than 6.2% and the accuracy ranged from 90.0% to 105.7%. The limit of quantification (LOQ) was 20.0–40.0ng/mL and the limit of detection (LOD) was 3.0–25.0ng/mL. With this method, low levels of ganoderic acids in the fruiting bodies of Ganoderma sinense and Ganoderma applanatum were accurately quantified for the first time. Importantly, the method allows unequivocal quantification of the five ganoderic acids in the spores and fruiting bodies of Ganoderma lucidum, whereas the previously published methods have lacked the capability. The method presented will be a powerful tool for quality control of Ganoderma lucidum and its related species. [Copyright &y& Elsevier]

[Display omitted] • An UPLC―MS/MS method for investigating the pharmacokinetics of JLZS was developed. • Fast quantification of seven bioactive components in rat plasma was performed. • LLOQs of 0.08―3.09 ng/mL were achieved with consumption of only 50 μL of plasma. • Pharmacokinetic compatibility of RC and FT in JLZS was studied for the first time. Jinlingzi San (JLZS), composed of Fructus Toosendan (FT) and Rhizoma Corydalis (RC), is a classical traditional Chinese medicine prescription for regulating Qi to relieve pain. The present study investigated the pharmacokinetic compatibility of FT and RC in JLZS. A fast, selective and sensitive UPLC ― MS/MS method for simultaneous determination of one limonoid (toosendanin), four tertiary alkaloids (corydaline, tetrahydropalmatine, tetrahydrocoptisine, tetrahydroberberine) and two quaternary alkaloids (palmatine, dehydrocorydaline) in rat plasma was established and fully validated. The plasma samples were pretreated by a fast protein precipitation and chromatographed using a 1.7-μm C18 column and 0.1 % formic acid―water and acetonitrile via gradient elution with a run time of 3.7 min. Multiple reaction monitoring mode with positive electrospray ionization was adopted to detect the analytes and internal standard (diphenhydramine). The lower limits of quantification were 0.08 ― 3.09 ng/mL using only 50 μL of plasma sample. Using the proposed method, the pharmacokinetic differences of seven bioactive components in rats after administration of JLZS and the single herb (FT or RC) were investigated. The results showed that the elimination of toosendanin and alkaloids decreased significantly in the JLZS group (p < 0.05) compared with the single herb group, and the exposure of the alkaloids increased in some degree. The study demonstrated the synergistic effect of combining FT with RC on the pharmacokinetics of seven bioactive components and provided new information for a better understanding of the compatibility mechanism of JLZS. [ABSTRACT FROM AUTHOR]

• Enantiomeric separation of seven profens on Chiralpak ID column. • Enantioselective residues determination of profens enantiomers in fish samples. • Solid phase extraction was used as a pretreatment technique for sample preparation and clean-up. In this work, enantiomeric separation of nine non-steroidal anti-inflammatory drugs including ibuprofen, indoprofen, pranoprofen, flurbiprofen, ketoprofen, carprofen, naproxen, loxoprofen and etodolac was investigated by HPLC combining with four polysaccharide based chiral stationary phases (Chiralpak IA, Chiralpak IB, Chiralpak IC and Chiralpak ID). The effect of various types of the mobile phase, acidic additive types, as well as mobile phase pH on enantiomeric separation was evaluated and optimized in detail. Chiralpak ID showed the best enantioselectivity towards seven of the above nine chiral drugs. Additionally, a sensitive and simple method for simultaneous enantioselective determination of indoprofen, flurbiprofen, carprofen and naproxen enantiomers in fish tissues based on C18 solid phase extraction (SPE) with chiral liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) on Chiralpak ID was established. Method validation showed that good linearity (R2 > 0.99) for each enantiomer with the limit of quantification in the range of 2–10 ng g−1 was obtained. Recoveries of the studied profens enantiomers in fish tissues were 82.6% - 106.7% with RSD less than 8.2% at three concentration levels. The proposed method was applied to the real fish samples analysis, providing a reference to fully evaluate the risks of these drug enantiomers in food or environmental samples. [ABSTRACT FROM AUTHOR]