A new issue of this journal has just been published. To see abstracts of the papers it contains (with links through to the full papers) click here:
Selected papers from the latest issue:
Analytical method development for synthesized conjugated metabolites of trans-resveratrol, and application to pharmacokinetic studies
12 March 2012, 09:25:55
Publication year: 2012
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Otito F. Iwuchukwu, Satish Sharan, Daniel J. Canney, Swati Nagar
Trans-3,5,4′-trihydroxystilbene (trans-resveratrol, RES) exhibits very low bioavailability due to extensive conjugative metabolism. Whether RES metabolites exhibit pharmacologic activity is of great interest. The present study aimed at synthesis of monoconjugates of RES – the 3- and 4′ monosulfates (R3S and R4′S), and the 3- and 4′ monoglucuronides (R3G and R4′G). Synthesis, purification, and yield are described. Synthesized metabolites were utilized to develop a sensitive LC–MSn assay for direct quantitation of all analytes. The assay was validated for intra- and inter-day precision and accuracy. Synthesis of RES conjugates and development and validation of a sensitive bioanalytical assay were applied to pharmacokinetic evaluation of RES and its circulating monoconjugates in C57BL mice. The study is a first report of direct quantitation of RES monosulfates and monoglucuronides. These results will aid in characterizing the disposition of RES and its major or active metabolites in vivo.
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Otito F. Iwuchukwu, Satish Sharan, Daniel J. Canney, Swati Nagar
Trans-3,5,4′-trihydroxystilbene (trans-resveratrol, RES) exhibits very low bioavailability due to extensive conjugative metabolism. Whether RES metabolites exhibit pharmacologic activity is of great interest. The present study aimed at synthesis of monoconjugates of RES – the 3- and 4′ monosulfates (R3S and R4′S), and the 3- and 4′ monoglucuronides (R3G and R4′G). Synthesis, purification, and yield are described. Synthesized metabolites were utilized to develop a sensitive LC–MSn assay for direct quantitation of all analytes. The assay was validated for intra- and inter-day precision and accuracy. Synthesis of RES conjugates and development and validation of a sensitive bioanalytical assay were applied to pharmacokinetic evaluation of RES and its circulating monoconjugates in C57BL mice. The study is a first report of direct quantitation of RES monosulfates and monoglucuronides. These results will aid in characterizing the disposition of RES and its major or active metabolites in vivo.
A rapid LC–MS/MS method for the quantitation of a series of benzonaphthyridine derivatives: Application to in vivo pharmacokinetic and lipophilicity studies in drug development
12 March 2012, 09:25:55
Publication year: 2012
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Pradeep B. Lukka, James W. Paxton, Graham J. Atwell, Philip Kestell, Bruce C. Baguley
Drug lipophilicity is a vital physicochemical parameter that influences drug absorption, distribution, metabolism, excretion and toxicology. A comparative study of a homologous series based on a pharmaceutically active drug represents a powerful approach to the study of the effects of drug lipophilicity. We have developed a rapid and sensitive LC–MS/MS method suitable for such a homologous series and applied it to a series of DNA binding benzonaphthyridine-based antitumour drugs of differing lipophilicity. The method used a gradient elution with a run time of 7min for simultaneous quantitation of five analogues in a pooled sample. Method validation was carried out in plasma (human and mouse) and mouse tissues (brain, heart, kidney, liver and lung). It had a limit of quantitation of 0.001μmol/L and was linear (0.001–0.3μmol/L) in all matrices with acceptable intra- and inter-assay precision and accuracy. This method allowed the pharmacokinetic parameters of these compounds in mice to be related to their lipophilicity as determined by their partition coefficient (Log D). Both the plasma CL (r =0.95; P =2×10−7) and V ss (r =0.95; P =2×10−7) exhibited a significant positive correlation with Log D values after intravenous bolus administration to mice. Consequently the plasma mean residence time for each of these five analogues decreased with increasing lipophilicity. There was also a significant positive correlation (r =0.91; P =2×10−7) between Log D values and the brain to plasma AUC ratio indicating the importance of lipophilicity in the distribution of these compounds into the brain tissue.
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Pradeep B. Lukka, James W. Paxton, Graham J. Atwell, Philip Kestell, Bruce C. Baguley
Drug lipophilicity is a vital physicochemical parameter that influences drug absorption, distribution, metabolism, excretion and toxicology. A comparative study of a homologous series based on a pharmaceutically active drug represents a powerful approach to the study of the effects of drug lipophilicity. We have developed a rapid and sensitive LC–MS/MS method suitable for such a homologous series and applied it to a series of DNA binding benzonaphthyridine-based antitumour drugs of differing lipophilicity. The method used a gradient elution with a run time of 7min for simultaneous quantitation of five analogues in a pooled sample. Method validation was carried out in plasma (human and mouse) and mouse tissues (brain, heart, kidney, liver and lung). It had a limit of quantitation of 0.001μmol/L and was linear (0.001–0.3μmol/L) in all matrices with acceptable intra- and inter-assay precision and accuracy. This method allowed the pharmacokinetic parameters of these compounds in mice to be related to their lipophilicity as determined by their partition coefficient (Log D). Both the plasma CL (r =0.95; P =2×10−7) and V ss (r =0.95; P =2×10−7) exhibited a significant positive correlation with Log D values after intravenous bolus administration to mice. Consequently the plasma mean residence time for each of these five analogues decreased with increasing lipophilicity. There was also a significant positive correlation (r =0.91; P =2×10−7) between Log D values and the brain to plasma AUC ratio indicating the importance of lipophilicity in the distribution of these compounds into the brain tissue.
Development of a method for the determination of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine of nonsmokers and smokers using liquid chromatography/tandem mass spectrometry
12 March 2012, 09:25:55
Publication year: 2012
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Hongwei Hou, Xiaotao Zhang, Yongfeng Tian, Gangling Tang, Yulan Liu, Qingyuan Hu
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is an efficient biomarker of tobacco-specific carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The ability to monitor biomarker concentrations is very important in understanding potential cancer risk. An analytical method using molecularly imprinted polymer (MIP) column coupled with liquid chromatography/tandem mass spectrometry (LC–MS/MS) for the determination of total NNAL in human urine was developed and validated. The combination of MIP column extraction and LC–MS/MS can provide a high sensitive and relatively simple analytical method. The limit of detection (LOD) was 0.30pg/ml and analysis time was 6min. The method has been applied to urine samples of 36 nonsmokers and 207 smokers. NNAL was found to be significantly higher in the urine of smokers compared with nonsmokers. Compared with smokers with blended cigarettes, Chinese virginia cigarettes smokers had low urinary NNAL levels. There was a direct association between the 24-h mouth-level exposure of carcinogen NNK from cigarette smoking and the concentration of NNAL in the urine of smokers. However, there was not a positive correlation between urinary total NNAL levels in 24h and tar. Total urinary NNAL is a valuable biomarker for monitoring exposure to carcinogenic NNK in smokers and in nonsmokers. A prediction model of cigarette smoke NNK and urinary average NNAL levels in 24h was established (y =2.8987x −245.38, r 2 =0.9952, n =204).
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Hongwei Hou, Xiaotao Zhang, Yongfeng Tian, Gangling Tang, Yulan Liu, Qingyuan Hu
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is an efficient biomarker of tobacco-specific carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The ability to monitor biomarker concentrations is very important in understanding potential cancer risk. An analytical method using molecularly imprinted polymer (MIP) column coupled with liquid chromatography/tandem mass spectrometry (LC–MS/MS) for the determination of total NNAL in human urine was developed and validated. The combination of MIP column extraction and LC–MS/MS can provide a high sensitive and relatively simple analytical method. The limit of detection (LOD) was 0.30pg/ml and analysis time was 6min. The method has been applied to urine samples of 36 nonsmokers and 207 smokers. NNAL was found to be significantly higher in the urine of smokers compared with nonsmokers. Compared with smokers with blended cigarettes, Chinese virginia cigarettes smokers had low urinary NNAL levels. There was a direct association between the 24-h mouth-level exposure of carcinogen NNK from cigarette smoking and the concentration of NNAL in the urine of smokers. However, there was not a positive correlation between urinary total NNAL levels in 24h and tar. Total urinary NNAL is a valuable biomarker for monitoring exposure to carcinogenic NNK in smokers and in nonsmokers. A prediction model of cigarette smoke NNK and urinary average NNAL levels in 24h was established (y =2.8987x −245.38, r 2 =0.9952, n =204).
Methods to measure the binding of therapeutic monoclonal antibodies to the human Fc receptor FcγRIII (CD16) using real time kinetic analysis and flow cytometry
12 March 2012, 09:25:55
Publication year: 2012
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Alice Harrison, Zhe Liu, Schona Makweche, Kevin Maskell, Hong Qi, Geoff Hale
Two different methods have been developed to measure the binding of therapeutic antibodies to the low affinity human Fc receptor FcγRIII (CD16). The first measures binding of antibody to recombinant soluble receptor by surface plasmon resonance and the second uses flow cytometry to measure antibody binding to cells which express the receptor. Both methods have been formatted as parallel line assays and show high levels of accuracy, precision and linearity, making them suitable for comparability, potency and stability assays. They are both readily able to detect structural differences such as glycosylation, which affect Fc receptor binding. The same approaches can be used to measure the binding of any antibody to any Fc receptor. These assays show greater internal precision and long-term reproducibility than traditional cell-based assays such as antibody-dependent cell-mediated cytotoxicity. A combinational approach with a target binding might be appropriate for routine drug batch release as these assays are likely to be significantly more sensitive to small changes in drug structure or activity.
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Alice Harrison, Zhe Liu, Schona Makweche, Kevin Maskell, Hong Qi, Geoff Hale
Two different methods have been developed to measure the binding of therapeutic antibodies to the low affinity human Fc receptor FcγRIII (CD16). The first measures binding of antibody to recombinant soluble receptor by surface plasmon resonance and the second uses flow cytometry to measure antibody binding to cells which express the receptor. Both methods have been formatted as parallel line assays and show high levels of accuracy, precision and linearity, making them suitable for comparability, potency and stability assays. They are both readily able to detect structural differences such as glycosylation, which affect Fc receptor binding. The same approaches can be used to measure the binding of any antibody to any Fc receptor. These assays show greater internal precision and long-term reproducibility than traditional cell-based assays such as antibody-dependent cell-mediated cytotoxicity. A combinational approach with a target binding might be appropriate for routine drug batch release as these assays are likely to be significantly more sensitive to small changes in drug structure or activity.
Identification of major compounds in rat bile after oral administration of total triterpenoids of Ganoderma lucidum by high-performance liquid chromatography with electrospray ionization tandem mass spectrometry
12 March 2012, 09:25:55
Publication year: 2012
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Xiao-Yu Guo, Jian Han, Min Ye, Xiao-Chi Ma, Xuan Shen, Bin-Bin Xue, Qing-Ming Che
Triterpenoids are the main bioactive components of Ganoderma lucidum, a famous traditional Chinese medicine. After oral administration of total triterpenoids of G. lucidum (TTGL), the rat bile was analyzed by high-performance liquid chromatography coupled with diode array detection and electrospray ion trap tandem mass spectrometry (HPLC-DAD–ESI-MS n ) and liquid chromatography coupled with electrospray ionization hybrid ion trap and time-of-flight mass spectrometry (LC–ESI-IT-TOF/MS). From rat bile and TTGL samples, a total of 31 triterpenoids, including seven new compounds, were identified or tentatively characterized based on their fragmentation behaviors. Among them, 22 triterpenoids were identified from TTGL and 29 triterpenoids were detected from rat bile after oral administration of TTGL. The results indicated that the majority of triterpenoids detected in TTGL extract could be excreted through rat bile. It is the first report on excretion of total triterpenoids of G. lucidum in rat bile.
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Xiao-Yu Guo, Jian Han, Min Ye, Xiao-Chi Ma, Xuan Shen, Bin-Bin Xue, Qing-Ming Che
Triterpenoids are the main bioactive components of Ganoderma lucidum, a famous traditional Chinese medicine. After oral administration of total triterpenoids of G. lucidum (TTGL), the rat bile was analyzed by high-performance liquid chromatography coupled with diode array detection and electrospray ion trap tandem mass spectrometry (HPLC-DAD–ESI-MS n ) and liquid chromatography coupled with electrospray ionization hybrid ion trap and time-of-flight mass spectrometry (LC–ESI-IT-TOF/MS). From rat bile and TTGL samples, a total of 31 triterpenoids, including seven new compounds, were identified or tentatively characterized based on their fragmentation behaviors. Among them, 22 triterpenoids were identified from TTGL and 29 triterpenoids were detected from rat bile after oral administration of TTGL. The results indicated that the majority of triterpenoids detected in TTGL extract could be excreted through rat bile. It is the first report on excretion of total triterpenoids of G. lucidum in rat bile.
Interaction of antioxidant flavonoids with calf thymus DNA analyzed by spectroscopic and electrochemical methods
12 March 2012, 09:25:55
Publication year: 2012
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Ashwini H. Hegde, S.N. Prashanth, J. Seetharamappa
Mechanism of interaction of bioactive flavonoids, hesperitin (HES) and naringenin (NAR) with calf thymus deoxyribonucleic acid (DNA) was studied employing UV absorption, fluorescence, circular dichroism, melting temperature, fluorescence anisotropy and differential pulse voltammetric methods. The observed fluorescence quenching of DNA-ethidium bromide system by the flavonoid indicated the intercalative mode of binding between the flavonoid and DNA. Stern–Volmer plots have revealed the presence of static quenching mechanism. Binding and thermodynamic characteristics of interaction were evaluated. Melting temperature of DNA was found to be increased up to 5°C in the presence of the flavonoid indicating the stabilization of DNA double helix upon binding. CD and fluorescence anisotropic results have revealed the conformational changes in DNA upon binding to the flavonoid. The observed positive shift in peak potential and decreased peak current of the flavonoid in the presence of DNA further supported the intercalative mode of binding.
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Ashwini H. Hegde, S.N. Prashanth, J. Seetharamappa
Mechanism of interaction of bioactive flavonoids, hesperitin (HES) and naringenin (NAR) with calf thymus deoxyribonucleic acid (DNA) was studied employing UV absorption, fluorescence, circular dichroism, melting temperature, fluorescence anisotropy and differential pulse voltammetric methods. The observed fluorescence quenching of DNA-ethidium bromide system by the flavonoid indicated the intercalative mode of binding between the flavonoid and DNA. Stern–Volmer plots have revealed the presence of static quenching mechanism. Binding and thermodynamic characteristics of interaction were evaluated. Melting temperature of DNA was found to be increased up to 5°C in the presence of the flavonoid indicating the stabilization of DNA double helix upon binding. CD and fluorescence anisotropic results have revealed the conformational changes in DNA upon binding to the flavonoid. The observed positive shift in peak potential and decreased peak current of the flavonoid in the presence of DNA further supported the intercalative mode of binding.
Determination of a novel TAZ modulator, 2-butyl-5-methyl-6-(pyridine-3-yl)-3-[2′-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl]-3H imidazo[4,5-b]pyridine] (TM-25659) in rat plasma by liquid chromatography–tandem mass spectrometry
12 March 2012, 09:25:55
Publication year: 2012
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Sung Heum Choi, Kyeong-Ryoon Lee, Jae-Chun Woo, Nak Jeong Kim, Dong Cheul Moon, Eun Sook Hwang, Sung-Hoon Ahn, Myung Ae Bae, Min-Sun Kim
TM-25659 compound, a novel TAZ modulator, is developed for the control of bone loss and obesity. TAZ is known to bind to a variety of transcription factors to control cell differentiation and organ development. A selective and sensitive method was developed for the determination of TM-25659 concentrations in rat plasma. The drug was measured by liquid chromatography–tandem mass spectrometry after liquid–liquid extraction with ethyl acetate. TM-25659 and the internal standard imipramine were separated on a Hypersil GOLD C18 column with a mixture of acetonitrile–ammonium formate (10mM) (90:10, v/v) as the mobile phase. The ions m/z 501.2→207.2 for TM-25659 and m/z 281.0→86.0 for imipramine in multiple reaction monitoring mode were used for the quantitation. The calibration range was 0.1–100μg/ml with a correlation coefficient greater than 0.99. The lower limit of quantitation of TM-25659 in rat plasma was 0.1μg/ml. The percent recoveries of TM-25659 and imipramine were 98.6% and 95.7% from rat plasma, respectively. The intra- and inter-batch precisions were 3.17–15.95% and the relative error was 0.38–10.82%. The developed assay was successfully applied to a pharmacokinetic study of TM-25659 administered intravenously (10mg/kg) to rats.
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Sung Heum Choi, Kyeong-Ryoon Lee, Jae-Chun Woo, Nak Jeong Kim, Dong Cheul Moon, Eun Sook Hwang, Sung-Hoon Ahn, Myung Ae Bae, Min-Sun Kim
TM-25659 compound, a novel TAZ modulator, is developed for the control of bone loss and obesity. TAZ is known to bind to a variety of transcription factors to control cell differentiation and organ development. A selective and sensitive method was developed for the determination of TM-25659 concentrations in rat plasma. The drug was measured by liquid chromatography–tandem mass spectrometry after liquid–liquid extraction with ethyl acetate. TM-25659 and the internal standard imipramine were separated on a Hypersil GOLD C18 column with a mixture of acetonitrile–ammonium formate (10mM) (90:10, v/v) as the mobile phase. The ions m/z 501.2→207.2 for TM-25659 and m/z 281.0→86.0 for imipramine in multiple reaction monitoring mode were used for the quantitation. The calibration range was 0.1–100μg/ml with a correlation coefficient greater than 0.99. The lower limit of quantitation of TM-25659 in rat plasma was 0.1μg/ml. The percent recoveries of TM-25659 and imipramine were 98.6% and 95.7% from rat plasma, respectively. The intra- and inter-batch precisions were 3.17–15.95% and the relative error was 0.38–10.82%. The developed assay was successfully applied to a pharmacokinetic study of TM-25659 administered intravenously (10mg/kg) to rats.
Solid-state characterization of tacrine hydrochloride
12 March 2012, 09:25:55
Publication year: 2012
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Milena Sorrenti, Laura Catenacci, Giovanna Bruni, Barbara Luppi, Federica Bigucci, Giampiero Bettinetti
The present study deals with the physicochemical characterization of solid forms of tacrine monohydrochloride (TCR), a centrally active reversible acetylcholinesterase inhibitor for treating the symptoms of mild to moderate Alzheimer's disease, obtained by recrystallization of hot saturated solutions from different solvents. Recrystallization of the commercially available hydrate, TCR·H2O, from water, hydroalcoholic solutions with ethanol, n-propanol, methanol and isopropanol (1:1, v/v) and isopropanol/water (8:2, v/v) afforded a new dihydrate phase TCR·2H2O form I. The TCR samples obtained by desolvation of TCR·H2O and TCR·2H2O show temperature and melting enthalpy values very similar, thus confirming the existence of a unique anhydrous crystalline phase. Exposure of anhydrous TCR powder samples under different atmospheric conditions at room temperature, resulted in rehydration to TCR·H2O at 32% relative humidity (RH), whereas at 100% RH a new solid form of TCR·2H2O (TCR·2H2O form II), i.e. a polymorph of the dihydrate isolated by recrystallization, was obtained. Differential scanning calorimetry (DSC), simultaneous thermogravimetric analysis (TGA/DSC), and thermo optical analysis (TOA) with support from X-ray powder diffractometry (PXRD) and Fourier transform infrared spectroscopy (FT-IR), were used for the characterization of the isolated solid forms of TCR and monitoring the water uptake of anhydrous TCR.
Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 63
Milena Sorrenti, Laura Catenacci, Giovanna Bruni, Barbara Luppi, Federica Bigucci, Giampiero Bettinetti
The present study deals with the physicochemical characterization of solid forms of tacrine monohydrochloride (TCR), a centrally active reversible acetylcholinesterase inhibitor for treating the symptoms of mild to moderate Alzheimer's disease, obtained by recrystallization of hot saturated solutions from different solvents. Recrystallization of the commercially available hydrate, TCR·H2O, from water, hydroalcoholic solutions with ethanol, n-propanol, methanol and isopropanol (1:1, v/v) and isopropanol/water (8:2, v/v) afforded a new dihydrate phase TCR·2H2O form I. The TCR samples obtained by desolvation of TCR·H2O and TCR·2H2O show temperature and melting enthalpy values very similar, thus confirming the existence of a unique anhydrous crystalline phase. Exposure of anhydrous TCR powder samples under different atmospheric conditions at room temperature, resulted in rehydration to TCR·H2O at 32% relative humidity (RH), whereas at 100% RH a new solid form of TCR·2H2O (TCR·2H2O form II), i.e. a polymorph of the dihydrate isolated by recrystallization, was obtained. Differential scanning calorimetry (DSC), simultaneous thermogravimetric analysis (TGA/DSC), and thermo optical analysis (TOA) with support from X-ray powder diffractometry (PXRD) and Fourier transform infrared spectroscopy (FT-IR), were used for the characterization of the isolated solid forms of TCR and monitoring the water uptake of anhydrous TCR.
No comments:
Post a Comment