Publications by authors named "Haitham AlRabiah"

43 Publications

Development of novel univariate and multivariate validated chemometric methods for the analysis of dasatinib, sorafenib, and vandetanib in pure form, dosage forms and biological fluids.

Spectrochim Acta A Mol Biomol Spectrosc 2022 Jan 28;264:120336. Epub 2021 Aug 28.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

New precise, responsive and selective univariate and multivariate chemometric spectrophotometric methods were developed and validated for determination of vandetanib (VTB), dasatinib (DTB), and sorafenib (SFB) in pure form, tablets, spiked human (plasma and urine). Determination of these drugs is essential because of their therapeutic benefits. These methods included double divisor ratio spectra derivative univariate method and chemometric multivariate method including partial least-squares (PLS) and principal component regression (PCR). A novel univariate method was developed for the estimation of these drugs. This method depends on the UV-Spectrophotometric data for simultaneous analysis of a ternary overlapped mixture. The Double divisor ratio spectra derivative absorption minima at 358.4 nm was used for quantification of VTB, absorption maxima at 300.3 nm for quantification of DTB and absorption maxima at 259.8 nm for quantification of SFB. This method shown a linearity in the extent of 2-9 μg/mL for VTB and DTB and over the concentration range of 3-9 μg/mL SFB within correlation coefficient (r2) of 0.9999. This method was successfully applied to pure form, tablet dosage form, spiked human (urine and plasma). Chemometric PLS and PCR models were found to be linear in the range of 2-9, 2-9, and 3-9 μg/mL for VTB, DTB and SFB, respectively. These models were estimated using eighteen mixtures as calibration set and seven mixtures as validation set. In the original data, the minimum root mean square error of prediction (RMSEP) was 0.11, 0.09 and 0.09 for VTB, DTB and SFB by PLS and 0.05, 0.04 and 0.03 by PCR while in the derivative data, the RMSEP was 0.09, 0.10 and 0.09 by PLS and 0.06, 0.06 and 0.03, by PCR for VTB, DTB and SFB, respectively. These methods were applied for the determination of the drugs in pure form and dosage form. Updating PLS model permitted the determination of the VTB, DTB and SFB in spiked human urine, plasma and drug-dissolution test of their tablet.
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http://dx.doi.org/10.1016/j.saa.2021.120336DOI Listing
January 2022

LC-MS/MS method for the quantification of the anti-cancer agent infigratinib: Application for estimation of metabolic stability in human liver microsomes.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Aug 2;1179:122806. Epub 2021 Jul 2.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Electronic address:

Infigratinib (INF) is a novel small molecule, administered orally, which acts as a human fibroblast growth factor receptors (FGFRs) inhibitor. FGFRs are a family of receptor tyrosine kinases (RTK) reported to be upregulated in various tumor cell types. In 1 December 2020, BridgeBio Pharma Inc. announced FDA approval of INF as a New Drug Application, granting it Priority Review for the treatment of cholangiocarcinoma (CCA). Thus, the current study aimed to establish a validated LC-MS/MS method to estimate the INF concentration in the HLM matrix. In silico prediction of INF metabolism was done using the StarDrop® WhichP450™ module to verify its metabolic stability. An accurate and efficient LC-MS/MS analytical method was developed for INF metabolic stability evaluation. INF and duvelisib (DVB) (internal standard; IS) were eluted using an isocratic mobile phase with a C column as a stationary reversed phase. The established LC-MS/MS method showed a linear range over 5-500 ng/mL (r ≥ 0.9998) in human liver microsomes (HLMs). The sensitivity of the method was confirmed at its limit of quantification (4.71 ng/mL), and reproducibility was indicated by inter- and intra-day accuracy and precision (within 7.3%). The evaluation of INF metabolic stability was assessed, which reflected an intrinsic clearance of 23.6 µL/min/mg and in vitro half-life of 29.4 min. The developed approach in the current study is the first LC-MS/MS method for INF metabolic stability assessment. Application of the developed method in HLM in vitro studies suggests that INF has a moderate extraction ratio, indicating relatively good predicted oral bioavailability.
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http://dx.doi.org/10.1016/j.jchromb.2021.122806DOI Listing
August 2021

Synthesis and Photophysical Properties of Fluorescein Esters as Potential Organic Semiconductor Materials.

J Fluoresc 2021 Sep 21;31(5):1489-1502. Epub 2021 Jul 21.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.

Fluorescein (1), a known fluorescent tracer in microscopy with high photophysical properties, was esterified to have fluorescein ethyl ester (2) and O-ethyl-fluorescein ethyl ester (3) in excellent yields. All of them were investigated for the photophysical and electrochemical properties as potential organic semiconductor materials. Absorptions and emission spectra were taken in various solvents, compound 2 showed emission maxima at λ = 545 and compound 3 showed λ = 550 nm. Optical band gap energy (E) was calculated for 1-3 and the values were found in between 2.34 - 2.39 eV. Possibility of shifting emission maxima was studied in various pH (5-9) buffers, and finally the thermal stability was examined using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Increasing of conjugation system of 2 and 3 were studied by HOMO and LUMO distributions of 1-3. Experimental results showed that compounds 2 and 3 have excellent photophysical and electrochemical properties hence can be used as excellent organic semiconductor materials.
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http://dx.doi.org/10.1007/s10895-021-02789-yDOI Listing
September 2021

Simple and efficient spectroscopic-based univariate sequential methods for simultaneous quantitative analysis of vandetanib, dasatinib, and sorafenib in pharmaceutical preparations and biological fluids.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Nov 21;260:119987. Epub 2021 May 21.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. Electronic address:

Six sequential spectrophotometric-based univariate methods were developed and validated for the simultaneous estimation of three novel anticancer drugs vandetanib (VAN), dasatinib (DAS), and sorafenib (SOR) in a mixture, without the requirement for separation. These methods are novel, simple, precise, and accurate. Different steps including zero crossing, ratio-based, and/or derivative spectra were utilized to develop these analytical methods, namely, ratio difference spectrophotometric method, constant center method, successive derivative ratio method, isoabsorptive method, mean centering of the ratio spectra method, and derivative ratio spectrum-zero crossing method. The calibration curve linearity was ranged from 2 to 9, 2-9, and 3-9 μgmL for VAN, DAS, and SOR, respectively. These established methods were applied for the quantification of the three selected drugs in different biological fluids (spiked human plasma and urine) and pharmaceutical preparations. The aforementioned methods were established for the concurrent estimation of ternary and binary mixtures to enhance the signal-to-noise ratio. The results did not statistically differ from the other reported methods, indicating no significant difference in accuracy and precision at p = 0.05.
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http://dx.doi.org/10.1016/j.saa.2021.119987DOI Listing
November 2021

Rapid and sensitive LC-MS/MS method for the enantioanalysis of verapamil in rat plasma using superficially porous silica isopropyl-cyclofructan 6 chiral stationary phase after SPE: Application to a stereoselective pharmacokinetic study.

J Pharm Biomed Anal 2021 Jul 29;201:114108. Epub 2021 Apr 29.

Department of Pharmaceutics, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh, 11451, Saudi Arabia.

A novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the rapid and sensitive enantioselective analysis of verapamil (VER) in rat plasma was developed and validated using new superficially porous silica isopropyl-cyclofructan 6 chiral column (LarihcShell-P, LSP). The isocratic mobile phase composed of acetonitrile: trifluoroacetic acid: 10 mM ammonium formate (100 : 0.1 : 0.1, v/v/v) at a flow rate of 0.3 mL/min was applied. Sulpride was utilized as the internal standard (IS). Positive multiple reaction monitoring (MRM) mode was used for mass spectrometry analysis, and the process of analysis was run for 5.2 min. The (S)-(-)- and (R)-(+)-VER enantiomers with the IS were extracted from plasma by using solid-phase extraction (SPE) procedure before the analysis. The C18 cartridge gave good recovery rates for both enantiomers without interference from plasma endogenous. The developed assay was successfully validated following the US-FDA guidelines. The method was linear over concentration ranges of 0.5-500 ng/mL (r ≥ 0.997) for each enantiomer (plasma). The lower limits of quantification (LLOQ) for both isomers were 0.5 ng/mL. The intra- and inter-day relative standard deviations (RSD) were less than 8.7 % and the recoveries of (S)-(-)- and (R)-(+)-VER at three spiked levels of 1.5, 250.0 and 450.0 ranged from 92.0%-98.6%. The developed assay was effectively applied in monitoring the stereoselective pharmacokinetic study of VER enantiomers in rat plasma following oral administration of racemic VER. The pharmacokinetic parameters revealed that (S)-(-)-VER demonstrated prominently higher C and AUC values than (R)-(+)-enantiomer. The newly developed approach is the first chiral LC-MS/MS for the quantification of (S)-(-)- and (R)-(+)-VER utilizing superficially porous silica isopropyl-cyclofructan 6 chiral column in rat plasma after SPE.
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http://dx.doi.org/10.1016/j.jpba.2021.114108DOI Listing
July 2021

Charge Transfer Complexes of Ketotifen with 2,3-Dichloro-5,6-dicyano--benzoquinone and 7,7,8,8-Tetracyanoquodimethane: Spectroscopic Characterization Studies.

Molecules 2021 Apr 2;26(7). Epub 2021 Apr 2.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

The reactions of ketotifen fumarate (KT) with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as π acceptors to form charge transfer (CT) complexes were evaluated in this study. Experimental and theoretical approaches, including density function theory (DFT), were used to obtain the comprehensive, reliable, and accurate structure elucidation of the developed CT complexes. The CT complexes (KT-DDQ and KT-TCNQ) were monitored at 485 and 843 nm, respectively, and the calibration curve ranged from 10 to 100 ppm for KT-DDQ and 2.5 to 40 ppm for KT-TCNQ. The spectrophotometric methods were validated for the determination of KT, and the stability of the CT complexes was assessed by studying the corresponding spectroscopic physical parameters. The molar ratio of KT:DDQ and KT:TCNQ was estimated at 1:1 using Job's method, which was compatible with the results obtained using the Benesi-Hildebrand equation. Using these complexes, the quantitative determination of KT in its dosage form was successful.
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http://dx.doi.org/10.3390/molecules26072039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038309PMC
April 2021

Development and Validation of a Chiral Liquid Chromatographic Assay for Enantiomeric Separation and Quantification of Verapamil in Rat Plasma: Stereoselective Pharmacokinetic Application.

Molecules 2021 Apr 6;26(7). Epub 2021 Apr 6.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

A novel, fast and sensitive enantioselective HPLC assay with a new core-shell isopropyl carbamate cyclofructan 6 (superficially porous particle, SPP) chiral column (LarihcShell-P, LSP) was developed and validated for the enantiomeric separation and quantification of verapamil (VER) in rat plasma. The polar organic mobile phase composed of acetonitrile/methanol/trifluoroacetic acid/triethylamine (98:2:0.05: 0.025, ) and a flow rate of 0.5 mL/min was applied. Fluorescence detection set at excitation/emission wavelengths 280/313 nm was used and the whole analysis process was within 3.5 min, which is 10-fold lower than the previous reported HPLC methods in the literature. Propranolol was selected as the internal standard. The S-(-)- and R-(+)-VER enantiomers with the IS were extracted from rat plasma by utilizing Waters Oasis HLB C18 solid phase extraction cartridges without interference from endogenous compounds. The developed assay was validated following the US-FDA guidelines over the concentration range of 1-450 ng/mL (r ≥ 0.997) for each enantiomer (plasma) and the lower limit of quantification was 1 ng/mL for both isomers. The intra- and inter-day precisions were not more than 11.6% and the recoveries of S-(-)- and R-(+)-VER at all quality control levels ranged from 92.3% to 98.2%. The developed approach was successfully applied to the stereoselective pharmacokinetic study of VER enantiomers after oral administration of 10 mg/kg racemic VER to Wistar rats. It was found that S-(-)-VER established higher C and area under the concentration-time curve (AUC) values than the R-(+)-enantiomer. The newly developed approach is the first chiral HPLC for the enantiomeric separation and quantification of verapamil utilizing a core-shell isopropyl carbamate cyclofructan 6 chiral column in rat plasma within 3.5 min after solid phase extraction (SPE).
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http://dx.doi.org/10.3390/molecules26072091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038655PMC
April 2021

Identification and characterization of , , and reactive metabolites of tandutinib using liquid chromatography ion trap mass spectrometry.

Anal Methods 2021 01;13(3):399-410

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.

Tandutinib (TND) is a novel, oral small molecule designed for treating acute myeloid leukemia (AML) by inhibiting type III receptor tyrosine kinases. This study reports the use of in silico, in vivo, and in vitro methods to investigate the metabolism and possible metabolic bioactivation of TND. First, in silico metabolism of TND was assessed using the WhichP450™ module of the StarDrop® software to determine labile sites of metabolism in the TND chemical structure. Second, the XenoSite reactivity model, a web-based metabolism prediction software, was used to determine probable bioactive centers. Based on the in silico outcomes, a list of predicted metabolites and reactive intermediates were prepared. Third, in vitro and in vivo experiments were performed. In vitro TND metabolites were generated through incubation of TND with rat liver microsomes (RLMs). Another incubation of TND with RLMs was separately performed in the presence of GSH and KCN to check for the generation of reactive intermediates (soft and hard electrophiles). In vitro phase II metabolism was assessed by incubation of TND with isolated perfused rat hepatocytes. In vivo metabolism was investigated by oral gavage of TND (37 mg kg-1) in Sprague Dawley rats. Five in vitro phase I metabolites, one in vitro phase II and five reactive iminium intermediates (cyano adducts), six in vivo phase I, and one in vivo phase II metabolites of TND were characterized. The in vitro and in vivo metabolic pathways involved were O-dealkylation, α-hydroxylation, α-carbonyl formation, reduction, glucuronide, and sulfate conjugation. No GSH conjugate or its catabolic products were detected either in vitro or in vivo. Two cyclic tertiary rings of TND (piperazine and piperidine) were metabolically bioactivated to generate reactive iminium intermediates forming cyano adducts with KCN. The formed reactive intermediates may be the reason behind TND toxicity. In silico toxicological studies were performed for TND and its related (in vitro and in vivo) metabolites were evaluated using the DEREK software tool.
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http://dx.doi.org/10.1039/d0ay02106gDOI Listing
January 2021

Discrimination of bacteria using whole organism fingerprinting: the utility of modern physicochemical techniques for bacterial typing.

Analyst 2021 Feb 9;146(3):770-788. Epub 2020 Dec 9.

Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia.

Rapid and accurate classification and discrimination of bacteria is an important task and has been highlighted recently for rapid diagnostics using real-time results. Coupled with a recent report by Jim O'Neill [] that if left unaddressed antimicrobial resistance (AMR) in bacteria could kill 10 million people per year by 2050, which would surpass current cancer mortality, this further highlights the need for unequivocal identification of microorganisms. Whilst traditional microbiological testing has offered insights into the characterisation and identification of a wide range of bacteria, these approaches have proven to be laborious and time-consuming and are not really fit for purpose, considering the modern day speed and volume of international travel and the opportunities it creates for the spread of pathogens globally. To overcome these disadvantages, modern analytical methods, such as mass spectrometry (MS) and vibrational spectroscopy, that analyse the whole organism, have emerged as essential alternative approaches. Currently within clinical microbiology laboratories, matrix assisted laser desorption ionisation (MALDI)-MS is the method of choice for bacterial identification. This is largely down to its robust analysis as it largely measures the ribosomes which are always present irrespective of how the bacteria are cultured. However, MALDI-MS requires large amounts of biomass and infrared spectroscopy and Raman spectroscopy are attractive alternatives as these physicochemical bioanalytical techniques have the advantages of being rapid, reliable and cost-effective for analysing various types of bacterial samples, even at the single cell level. In this review, we discuss the fundamental applications, advantages and disadvantages of modern analytical techniques used for bacterial characterisation, classification and identification.
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http://dx.doi.org/10.1039/d0an01482fDOI Listing
February 2021

Development and validation of an HPLC-MS/MS method for the determination of filgotinib, a selective Janus kinase 1 inhibitor: Application to a metabolic stability study.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Oct 30;1154:122195. Epub 2020 May 30.

Department of Pharmaceutical Chemistry, College of pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Micro-analytical Laboratory, Applied Organic Chemistry Department, National Research Center, Dokki, Cairo, Egypt. Electronic address:

Filgotinibis aselective Janus kinase 1 inhibitor drug which is currently under investigation for the treatment of rheumatoid arthritis and Crohn s disease. The aim of the present study was to develop an accurate, simple and sensitive LC-MS/MS method for the determination of filgotinib (FLG) in human liver microsomes (HLMs) and its application to a metabolic stability study. Chromatographic separation was carried on using of a reversed phase C18 column. The mobile phase was mixture of acetonitrile and ammonium formate (10 mM, pH 3.8) (30:70, v/v), under isocratic elution at a flow rate of 0.3 mL/min. Veliparib was used as internal standard. FLG was extracted from HLMs by precipitation. An electrospray ionization source was used to assay of FLG. The assay of FLG at m/z 426 → 358 and 426 → 291 for FLG and IS at 245 → 145 and 245 → 84 was attained through MRM. The linearity of the investigated method was observed from 5 to 500 ng/mL (correlation coefficient r = 0.999). The LOD was 1.43 ng/mL, while the LOQ was 4.46 ng/mL. The investigated method exhibited good recovery (98.42-108.6%) and precision (ranged from 0.88% to 4.7%). The investigated method was successfully employed for a metabolic stability study of FLG in the HLMs matrix. The metabolic stability of FLG was evaluated by measuring two parameters, in vitro t (48.47 min) and intrinsic clearance (14.29μL/min/mg). The results of the metabolic study confirm that FLG is execrated from the human body at a slower rate compared to related tyrosine kinase inhibitors. Therefore, drug plasma levels and kidney function should be monitored due to potential bioaccumulation.
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http://dx.doi.org/10.1016/j.jchromb.2020.122195DOI Listing
October 2020

Development and Validation of an HPLC-UV Detection Assay for the Determination of Clonidine in Mouse Plasma and Its Application to a Pharmacokinetic Study.

Molecules 2020 Sep 8;25(18). Epub 2020 Sep 8.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

An accurate and simple HPLC-UV method has been developed for the determination of clonidine in mouse plasma. A reversed phase C18 Nova Pack column (125 mm × 4.6 mm i.d., × 3 μm particle size) was used as stationary phase. The mobile phase composition was a mixture of 0.1% diethylamine/acetonitrile (70:30, /) at pH 8 in an isocratic mode at flow rate was 1.0 mL/min. Detection was set at 210 nm. Tizanidine was used as an internal standard. The clonidine and tizanidine were extracted from plasma matrix using the deproteinization technique. The developed method exhibited a linear calibration range 100.0-2000 ng/mL and the lower limit of detection (LOD) and quantification (LOQ) were 31.0 and 91.9 ng/mL, respectively. The intra-day and inter-day accuracy and precision of the method were within 8.0% and 3.0%, respectively, relative to the nominal concentration. The developed method was validated with respect to linearity, accuracy, precision, and selectivity according to the US Food and drug guideline. Minimal degradation was demonstrated during the determination of clonidine under different stability conditions. The suggested method has been successfully applied during a pharmacokinetic study of clonidine in mouse plasma.
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http://dx.doi.org/10.3390/molecules25184109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571031PMC
September 2020

Spectroscopic and molecular docking studies reveal binding characteristics of nazartinib (EGF816) to human serum albumin.

R Soc Open Sci 2020 Jan 15;7(1):191595. Epub 2020 Jan 15.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.

The interactions of novel anti-cancer therapeutic agents with the different plasma and tissue components, specifically serum albumins, have lately gained considerable attention due to the significant influence of such interactions on the pharmacokinetics and/or -dynamics of this important class of therapeutics. Nazartinib (EGF 816; NAZ) is a new anti-cancer candidate proposed as a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that is being developed and clinically tested for the management of non-small cell lung cancer. The current study aimed to characterize the interaction between NAZ and human serum albumin (HSA) using experimental and theoretical approaches. Experimental results of fluorescence quenching of HSA induced by NAZ revealed the development of a statically formed complex between NAZ and HSA. Interpretation of the observed fluorescence data using Stern-Volmer, Lineweaver-Burk and double-log formulae resulted in binding constants for HSA-NAZ complex in the range of (2.34-2.81) × 10 M over the studied temperatures. These computed values were further used to elucidate thermodynamic attributes of the interaction, which showed that NAZ spontaneously binds to HSA with a postulated electrostatic force-driven interaction. This was further verified by theoretical examination of the NAZ docking on the HSA surface that revealed an HSA-NAZ complex where NAZ is bound to HSA Sudlow site I driven by hydrogen bonding in addition to electrostatic forces in the form of pi-H bond. The HSA binding pocket for NAZ was shown to encompass ARG 257, ARG 222, LYS 199 and GLU 292 with a total binding energy of -25.59 kJ mol.
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http://dx.doi.org/10.1098/rsos.191595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029911PMC
January 2020

A New Validated HPLC-MS/MS Method for Quantification and Pharmacokinetic Evaluation of Dovitinib, a Multi-Kinase Inhibitor, in Mouse Plasma.

Drug Des Devel Ther 2020 28;14:407-415. Epub 2020 Jan 28.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11459, Saudi Arabia.

Background: Dovitinib (TKI 258) is a small-molecule multi-kinase inhibitor for the treatment of different types of cancer. There is currently no validated method for its quantitative determination; therefore, we aimed to develop a reliable method to assay dovitinib.

Method And Results: An electrospray ionization tandem mass spectrometry (ESI-MS/MS) method was used to separate dovitinib using an analytical C18 column (50 × 2.1 mm, 1.8 μm) at 25°C. Bosutinib was used as the internal standard (IS). Dovitinib was extracted from mouse plasma using a precipitation procedure. The mobile phase consisted of 10 mM ammonium formate: acetonitrile (68:32, v/v, pH 4.3) run at a rate of 0.3 mL min. MS detection was performed in the positive ion mode. Multiple reaction monitoring transitions were 393→337 and 393→309 for dovitinib, and 530→141 and 530→113 for bosutinib. The investigated method was validated as a bio-analytical method based on FDA guidelines. The linearity of the developed method was over the range of 5-500 ng mL, coefficient of determination (r= 0.9998). The average intra-day recovery and relative standard deviation (RSD) of the quality control (QC) sample were 97.24% and 1.32%, whereas the overall inter-day accuracy and precision were 97.99% and 0.54%, respectively. Dovitinib was stable during sample storage and handling conditions. Furthermore, the dilution integrity of the method was demonstrated by good recovery (97-99%) and RSD values (0.5-0.7%).

Conclusion: This method was selectively sensitive and exhibited no matrix effect, with an acceptable accuracy and precision according to the FDA guidelines. The developed method could be efficiently used for pharmacokinetic studies of dovitinib.
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http://dx.doi.org/10.2147/DDDT.S223573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995292PMC
January 2021

New potentiometric sensors for methylphenidate detection based on host-guest interaction.

BMC Chem 2019 Dec 14;13(1):121. Epub 2019 Oct 14.

1Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451 Saudi Arabia.

The study aims to develop simple, sensitive, and selective methods for detecting methylphenidate in its bulk, dosage form and human urine. Sensing materials include β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), and 4-butylcalix[8]arene as ionophores or electroactive materials have been used for construction of sensors 1, 2, and 3, respectively; Potassium tetrakis (4-chlorophenyl)borate (KTpClPB) as an ion additive was used and dioctyl phthalate as a plasticizer. The sensors displayed a fast, stable response over a wide concentration range of methylphenidate (8 × 10 M to 1 × 10 M) with 10 M detection limit over the pH range of 4-8. The developed sensors displayed a Near-Nernstian cationic response for methylphenidate at 59.5, 51.37, and 56.5 mV/decade for sensors β-CD, γ-CD, or 4-butylcalix[8]arene respectively. Validation of the proposed sensors is supported by high accuracy, precision, stability, fast response, and long lifetimes, as well as selectivity for methylphenidate in the presence of different species. Sensitive and practical sensors for the determination of methylphenidate in bulk, in pharmaceutical forms and urine were developed and validated for routine laboratory use. The results were comparable to those obtained by HPLC method.
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http://dx.doi.org/10.1186/s13065-019-0634-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792245PMC
December 2019

Development of two different formats of heterogeneous fluorescence immunoassay for bioanalysis of afatinib by employing fluorescence plate reader and KinExA 3200 immunosensor.

Sci Rep 2019 10 14;9(1):14742. Epub 2019 Oct 14.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.

Afatinib (AFT) is a potent and highly selective drug used to treat various solid tumors including non-small cell lung cancer (NSCLC). To ensure safe and effective treatment of cancer patients with AFT, its plasma concentrations should be monitored. Thus, sensitive immunoassays are required for measuring AFT concentrations in plasma samples. In this study, two different formats of heterogeneous fluorescent immunoassays were developed and validated for AFT bioanalysis. These assays were microwell-based fluorescence immunoassay (FIA) using fluorescence plate reader and kinetic exclusion assay (KinExA) using KinExA 3200 immunosensor. Both FIA and KinExA were developed using the same reagents: mouse anti-AFT antibody, solid-phase immobilized AFT conjugated with bovine serum albumin protein (AFT-BSA), and goat anti-mouse IgG labelled with fluorescein isothiocyanate (FITC-IgG) for signal generation. The analytical performances of both assays were comparatively evaluated, and the results revealed that although both assays had comparable accuracies, KinExA was superior to FIA in terms of sensitivity and precisions. Moreover, both FIA and KinExA were better alternatives to the existing chromatographic methods for bioanalysis of AFT. The proposed FIA and KinExA are anticipated to effectively contribute in ensuring safe and effective treatment with AFT in clinical settings.
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http://dx.doi.org/10.1038/s41598-019-51288-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791937PMC
October 2019

Comparative study of β-cyclodextrin, γ-cyclodextrin and 4--butylcalix[8]arene ionophores as electroactive materials for the construction of new sensors for trazodone based on host-guest recognition.

Drug Des Devel Ther 2019 11;13:2283-2293. Epub 2019 Jul 11.

Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Background: Trazodone (TRZ) is a second-generation non-tricyclic antidepressant derived from a triazolopyridine derivative, which is mainly used to treat emotional disorders and conditions related to depressive disorders.

Purpose: This study investigated the design, development and characteristics of polyvinyl chloride (PVC) membrane sensors for trazodone HCl (TRZ).

Methods: The developed sensing membranes were constructed using β-cyclodextrin (β-CD; sensor 1), γ-cyclodextrin (γ-CD; sensor 2) or 4--butylcalix[8]arene (-BC8; sensor 3) ionophores as sensing materials in addition to ionic sites and dioctyl phthalate in the PVC matrix.

Results: Sensors 1, 2 and 3 displayed fast, stable and near-Nernstian response over a relatively wide trazodone concentration range (7.0×10-1×10, 5.0×10-1×10and 8.0×10-1.0×10 M, respectively), with detection limits of 2.2×10, 1.5×10 and 2.42×10 M, respectively in the pH range of 3.0-6.0. The sensors demonstrated good selectivity for TRZ in the presence of different ionic compounds. The accuracy and precision of the proposed sensors were assessed by the determination of 40.7 μg/ml of TRZ, which showed average recoveries of 99.6%, 99.1% and 98.5% with mean relative standard deviations of 2.4%, 2.5% and 2.6% for sensor 1, 2 and 3 respectively. Molecular modeling was used to calculate the host-guest binding energy. The lowest free binding energy was -6.243, -5.752 and -5.7105 kcal/mol for 1:1 stoichiometry host-guest complexes of trazodone and β-CD, γ-CD and -BC8, respectively, which was in-line with a Nernstian response.

Conclusion: The investigated methods can be applied for the determination of TRZ in pharmaceutical preparations. The results of investigated dosage-form of TRZ show good agreement with those using the US Pharmacopeia method.
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http://dx.doi.org/10.2147/DDDT.S201907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630091PMC
February 2020

Development and comparative evaluation of two immunoassay platforms for bioanalysis of crizotinib: A potent drug used for the treatment of non-small cell lung cancer.

Talanta 2019 Aug 10;201:217-225. Epub 2019 Apr 10.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. Electronic address:

This study describes, for the first time, the development of two platforms of competitive fluorescent immunoassays for bioanalysis of crizotinib (CZT), a potent drug used for the treatment of non-small cell lung cancer (NSCLC). These platforms were microwell-based heterogeneous fluoroimmunoassay (FIA) and a kinetic exclusion assay (KinExA) with KinExA™ 3200 immunosensor. Both FIA and KinExA were developed using same reagents; mouse anti-CZT antibody and a capturing reagent of CZT conjugated with bovine serum albumin (CZT-BSA). In the FIA, the CZT-BSA coated onto the microwells of the assay plate was present simultaneously in the assay mixture (CZT and its antibody). In the KinExA, the antibody was allowed to pre-equilibrate with CZT, and then the incubation mixture was rapidly passed through a microcolumn containing CZT-BSA coated onto polymethyl methacrylate (PMMA) beads. The analytical performances of both assays were comparatively evaluated in terms of assay working range, limit of detection, precision profile, and accuracy. The results revealed that KinExA yielded higher sensitivity and better precision than FIA; whereas, both assays had comparable accuracies. Both FIA and KinExA were superior to all the existing chromatographic methods for CZT in terms of the assay sensitivity, convenience, analysis throughputs. The proposed FIA and KinExA are anticipated to effectively contribute to the therapeutic drug monitoring (TDM) of CZT in clinical settings.
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http://dx.doi.org/10.1016/j.talanta.2019.04.013DOI Listing
August 2019

The use of active learning strategies in healthcare colleges in the Middle East.

BMC Med Educ 2019 May 14;19(1):143. Epub 2019 May 14.

Department of Clinical Pharmacy, College of Pharmacy, King Saud University, P.O. Box 2454, Riyadh, 11451, Saudi Arabia.

Background: Multiple studies have explored the use of active learning strategies among faculty members in different healthcare colleges worldwide, however, very few have described the use of these strategies in the Middle East. The aim of this study was to evaluate the extent of the implementation of active learning and its various techniques across different fields of healthcare education in various countries in the Middle East.

Methods: A Web-based questionnaire was developed to obtain information on the use of active learning methods. This survey was disseminated among faculty members in healthcare colleges in 17 Middle Eastern countries.

Results: Out of 22,734 online invitations that were sent to faculty members in different healthcare colleges, 2085 (9.17%) accepted the invitations, however, only 722 (34.63%) of those who agreed to participate filled out the questionnaire. Eighty-seven percent of the responders utilized at least one technique of active learning. Active learning was used more frequently by female responders. For example, 54.30% of the female responders reported using learning by teaching as one of their teaching methods compared to 41.30% of their male counterparts (p = 0.0005). The various forms of active learning were used at similar levels in both public and private healthcare colleges. Only minor differences were seen among different age groups or academic positions of the responders, but significant variabilities were noted among the several fields of healthcare education. For example, 61.54% of responders from the nursing faculty reported using reaction to videos as one of their teaching methods compared to 31.11% of their counterparts in the faculty of dentistry (p = 0.0021). The most frequently reported obstacles interfering with the effectuation of active learning include the lack of technical support and time constraints.

Conclusions: Although some barriers to the implementation of active learning exist, it is extensively used by faculty members in healthcare colleges in the Middle East.
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http://dx.doi.org/10.1186/s12909-019-1580-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518770PMC
May 2019

Topiramate: Comprehensive profile.

Profiles Drug Subst Excip Relat Methodol 2019 14;44:333-378. Epub 2019 Jan 14.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Topiramate, 2,3:4,5-di-O-isopropylidene-β-d-fructopyranose sulfamate, is a potent antiepileptic drug with a broad spectrum of activity. It is effective in both partial and generalized seizures. Topiramate was also found to have significant efficacy in migraine prevention with considerable reductions in the frequency of migraine headaches. The most common adverse events, which may accompany the use of topiramate, are paresthesia, fatigue, decreased appetite, nausea, diarrhea, weight decrease and taste perversion. The weight loss observed with the use of topiramate in obese, epileptic patients, afforded the approval of this drug as an anti-obesity medication. This action is thought to be based on the selective inhibition of mitochondrial carbonic anhydrase isoforms. This profile is prepared to discuss and explain physical characteristics, proprietary and nonproprietary names of topiramate. It also includes methods of preparation, thermal and spectral behavior and methods of analysis. Pharmacokinetics, metabolism, excretion and pharmacology together with its uses and applications are also discussed.
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http://dx.doi.org/10.1016/bs.podrm.2018.11.005DOI Listing
July 2019

Thiouracil: Comprehensive profile.

Profiles Drug Subst Excip Relat Methodol 2019 10;44:293-331. Epub 2019 Jan 10.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Thiouracil, 2-sulfanylidene-1H-pyrimidin-4-one, has been used as anti-thyroid, coronary vasodilator, and in congestive heart failure. It was found to cause agranulocytosis and it is suspected to be teratogenic and carcinogenic. Owing to its high frequency of adverse reactions, especially agranulocytosis, its use was abandoned in favor of other, less toxic drugs, such as propylthiouracil and methimazole. Thiouracil refers both to a specific molecule consisting of a sulfated uracil and a family of molecules based upon the structure. An important member of this family is propylthiouracil, which is a thiourea antithyroid drug that acts by blocking the production of thyroid hormones; it also inhibits the peripheral deiodination of thyroxine to tri-iodothyronine. This profile is prepared to discuss and explain physical and chemical properties, proprietary and nonproprietary names of thiouracil and propylthiouracil. It also includes uses and applications, methods of preparation, thermal and spectral behavior and methods of analysis. In addition, metabolism, excretion and pharmacology of propylthiouracil are also discussed.
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http://dx.doi.org/10.1016/bs.podrm.2018.11.006DOI Listing
July 2019

Levetiracetam.

Authors:
Haitham Alrabiah

Profiles Drug Subst Excip Relat Methodol 2019 25;44:167-204. Epub 2019 Mar 25.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

A comprehensive profile of levetiracetam is presented in this chapter which includes its description, formula, elemental analysis, appearance, uses and applications. Different earlier studies included for example methods of synthesis are described with its typical structural schemes. The profile also listed the drug's physical characteristics indicating its solubility, X-ray powder diffraction pattern, thermal methods of analysis as well as its spectroscopic characteristics. Different methods of analysis which includes compendial method of analysis, as well as reported method of analysis which include spectrophotometry, spectrofluorometry, electrochemical method, chromatographic method, and immunoassay method of analysis. The study was include drug stability, clinical pharmacology, e.g., mechanism of action, pharmacokinetic study. Around 70 references are recorded as a proof of this chapter.
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http://dx.doi.org/10.1016/bs.podrm.2019.02.003DOI Listing
July 2019

Validated LC-MS/MS assay for quantification of the newly approved tyrosine kinase inhibitor, dacomitinib, and application to investigating its metabolic stability.

PLoS One 2019 4;14(4):e0214598. Epub 2019 Apr 4.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia.

Dacomitinib (DMB) is a second-generation irreversible tyrosine kinase inhibitor (TKI) that is claimed to overcome the disadvantages of the resistance reported for first-line epidermal growth factor receptor (EGFR) TKIs. Towards the end of 2018, the US Food and Drug Administration approved DMB in the form of VIZIMPRO tablets. In the current study, a validated LC-MS/MS assay was established for DMB quantification in rat liver microsomes (RLMs) with application to the drug metabolic stability assessment. Chromatographic resolution of DMB and lapatinib (internal standard) was achieved using an isocratic mobile phase and a reversed-phase C18 column. The linearity of the established LC-MS/MS assay ranged from 2 to 500 ng/mL with r2 ≥ 0.9999. The limit of detection (LOD) and limit of quantification (LOQ) were 0.35 and 1.1 ng/mL, respectively. The precision and accuracy (both intra-day and inter-day) were 0.84-3.58% and 92.2-100.32%, respectively. The metabolic stability of DMB in the RLM matrix was estimated by calculating two parameters, in vitro t1/2 (0.97 mL/min/kg) and intrinsic clearance (157.5 min). Such values infer that DMB would be excreted very slowly from the human body, which might lead to possible bioaccumulation. To the best of our knowledge, this is the first method for DMB analysis in RLMs with metabolic stability estimation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214598PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448865PMC
January 2020

Automated flow fluorescent noncompetitive immunoassay for measurement of human plasma levels of monoclonal antibodies used for immunotherapy of cancers with KinExA™ 3200 biosensor.

Talanta 2019 Jan 7;192:331-338. Epub 2018 Sep 7.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. Electronic address:

This study describes, for the first time, the development of an automated sensitive flow fluorescent noncompetitive immunoassay based on kinetic-exclusion analysis (KinExA) for the quantitative determination of human plasma levels of monoclonal antibodies (mAbs) used for cancer immunotherapy. The assay was adapted on KinExA™ 3200 biosensor and optimized and validated for bevacizumab (BEV) and cetuximab (CET), as representative examples of the mAbs, using their specific antigens. These antigens were the human vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) for BEV and CET, respectively. The limits of detection were 1.28 and 52.64 ng mL for BEV and CET, respectively. The accuracy of the assay was demonstrated with analytical recovery of analytes from spiked plasma at 96.2-104.3 and 96.8-105.3% for BEV and CET, respectively. The precision of the assay was satisfactory as shown by relative standard deviation (RSD) at 2.2-5.7 and 2.5-6.1% for assay of BEV and CET, respectively. The high sensitivity of the assay allowed the use of very small volumes (~ 1 µL) of plasma sample for analysis. Automated analysis by the proposed KinExA-based assay facilitates the processing of large numbers of mAbs-containing specimens in studies of pharmacokinetics (PK), pharmacodynamics (PD), and therapeutic drug monitoring (TDM) of therapeutic mAbs. The proposed assay can be used to overcome the problems encountered in the existing conventional immunoassays for mAbs.
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http://dx.doi.org/10.1016/j.talanta.2018.09.014DOI Listing
January 2019

Cellular responses of hyaluronic acid-coated chitosan nanoparticles.

Toxicol Res (Camb) 2018 Sep 23;7(5):942-950. Epub 2018 May 23.

National Center for Pharmaceuticals , Life science and Environment Research Institute , King Abdulaziz City for Science and Technology (KACST) , P.O. Box 6086 , Riyadh 11461 , Saudi Arabia . Email:

In recent years, nanotechnology has been proven to offer promising biomedical applications for diagnostics and drug delivery, stressing the importance of thoroughly investigating the biocompatibility of potentially translatable nanoparticles (NPs). Herein, we report the cellular responses of uncoated chitosan NPs (CS NPs) and hyaluronic acid-coated chitosan NPs (HA-CS NPs) when introduced into Chinese hamster ovary cells (CHO-K1) in a dose-dependent manner (2.5, 0.25, 0.025, 0.0025, and 0.00025 mg mL) at two time points (24 and 48 h). MTS assay, cell proliferation, showed a decrease in the viability of cells when treated with 0.25 and 2.5 mg mL CS NPs. When exposed to high doses of CS NPs, the lactate dehydrogenase (LDH) enzyme started to leak out of the cells and the cellular levels of mitochondrial potentials were significantly reduced accompanied by a high production of intracellular reactive oxygen species (ROS). Our study provides molecular evidence of the biocompatibility offered by HA-CS NPs, through ROS scavenging capabilities rescuing cells from the oxidative stress, showing no observed cellular stress and thereby revealing the promising effect of anionic hyaluronic acid to significantly reduce the cytotoxicity of CS NPs. Our findings are important to accelerate the translation and utilization of HA-CS NPs in drug delivery, demonstrating the pronounced effect of surface modifications on modulating the biological responses.
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http://dx.doi.org/10.1039/c8tx00041gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116812PMC
September 2018

LC-MS/MS reveals the formation of iminium and quinone methide reactive intermediates in entrectinib metabolism: In vivo and in vitro metabolic investigation.

J Pharm Biomed Anal 2018 Oct 22;160:19-30. Epub 2018 Jul 22.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt. Electronic address:

Entrectinib (RXDX-101) is orally available inhibitor of the tyrosine kinases including tropomyosin receptor kinases (Trk) A-C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK), with potential antineoplastic activity. Entrectinib (ENB) granted breakthrough designation by FDA for NTRK + Solid tumors. In vitro metabolism of ENB generates quinone methide and iminium reactive intermediates that were captured by potassium cyanide and GSH, respectively forming stable conjugates that were characterized by LC-MS/MS. Seven in vitro ENB metabolites were identified through four metabolic reactions including hydroxylation, N-dealkylation, N-oxidation and reduction. Furthermore, four reactive intermediates including two quinone methide and two iminium ions were detected and the bioactivation mechanisms were supposed. In vivo metabolism of ENB was done by giving single oral dose (35.2 mg/kg) to Sprague Dawley rats. In vivo metabolism generates five phase I metabolites similar to in vitro metabolism except no metabolic reactions were identified on indazole ring. One phase II metabolite was characterized in in vivo metabolism of ENB resulted from glucuronidation of hydroxyl metabolite of ENB. Reporting these data for ENB is very crucial in the development stage. Reviewing literatures revealed the absence of previous articles have been done for the ENB in vitro or in vivo metabolism study or structural characterization of the formed reactive intermediates.
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http://dx.doi.org/10.1016/j.jpba.2018.07.032DOI Listing
October 2018

Development and validation of generic heterogeneous fluoroimmunoassay for bioanalysis of bevacizumab and cetuximab monoclonal antibodies used for cancer immunotherapy.

Talanta 2018 Oct 28;188:562-569. Epub 2018 May 28.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. Electronic address:

This study describes, for the first time, the development and validation of a highly selective and sensitive heterogeneous fluoroimmunoassay (FIA) for the bioanalysis of two monoclonal antibodies (mAbs) used for cancer immunotherapy: bevacizumab (BEV) and cetuximab (CET). The assay combines reliable non-competitive binding of BEV and CET to their specific cell receptor proteins (human vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), respectively) with the highly specific fluorescence activity of the fluorescein isothiocyanate labeled anti-human IgG (FITC-IgG) used as label. The limits of detection were 14.14 and 1.27 × 10 ng mL for BEV and CET, respectively. The accuracy and precision of the assay were demonstrated. The assay is simple, convenient, and requires very small volume (~ 5 µL) of plasma sample for analysis. The assay can offer high throughput analysis in clinical settings when modern microplates of multiplies of 96 (up to 6144-wells) are used and/or integrated as a part of automated robotic system. The proposed assay can be used for routine clinical bioanalysis of mAbs with potential application in pharmacokinetics, pharmacodynamics and therapeutic drug monitoring (TDM).
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http://dx.doi.org/10.1016/j.talanta.2018.05.091DOI Listing
October 2018

pH plays a role in the mode of action of trimethoprim on Escherichia coli.

PLoS One 2018 13;13(7):e0200272. Epub 2018 Jul 13.

School of Chemistry and Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom.

Metabolomics-based approaches were applied to understand interactions of trimethoprim with Escherichia coli K-12 at sub-minimum inhibitory concentrations (MIC≈0.2, 0.03 and 0.003 mg L-1). Trimethoprim inhibits dihydrofolate reductase and thereby is an indirect inhibitor of nucleic acid synthesis. Due to the basicity of trimethoprim, two pH levels (5 and 7) were selected which mimicked healthy urine pH. This also allowed investigation of the effect on bacterial metabolism when trimethoprim exists in different ionization states. UHPLC-MS was employed to detect trimethoprim molecules inside the bacterial cell and this showed that at pH 7 more of the drug was recovered compared to pH 5; this correlated with classical growth curve measurements. FT-IR spectroscopy was used to establish recovery of reproducible phenotypes under all 8 conditions (3 drug levels and control in 2 pH levels) and GC-MS was used to generate global metabolic profiles. In addition to finding direct mode-of-action effects where nucleotides were decreased at pH 7 with increasing trimethoprim levels, off-target pH-related effects were observed for many amino acids. Additionally, stress-related effects were observed where the osmoprotectant trehalose was higher at increased antibiotic levels at pH 7. This correlated with glucose and fructose consumption and increase in pyruvate-related products as well as lactate and alanine. Alanine is a known regulator of sugar metabolism and this increase may be to enhance sugar consumption and thus trehalose production. These results provide a wider view of the action of trimethoprim. Metabolomics indicated alternative metabolism areas to be investigated to further understand the off-target effects of trimethoprim.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200272PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044521PMC
January 2019

LC-ESI-MS/MS identification and characterization of ponatinib in vivo phase I and phase II metabolites.

Clin Chim Acta 2018 Oct 30;485:144-151. Epub 2018 Jun 30.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Ponatinib (Iclusig®) is a multi-targeted tyrosine kinase inhibitor (TKIs). It is active against T315I and other BCR-ABL mutants. Investigation of in vivo metabolism of ponatinib was done using Sprague Dawley rats by giving one oral dose of PNT (4.7 mg/kg) to each rat and urine samples were gathered at several time intervals from dosing. Filteration of urine samples was done through 0.45 μm syringe filters. Phase separation using ACN was applied for extraction of ponatinib related metabolites. Characterization and identification of one in vivo phase II metabolite and thirteen in vivo phase I of PNT were done using LC-MS/MS. Phase I metabolic reactions were reduction, N-demethylation, hydroxylation, N-oxidation, oxidation and amide hydrolysis. Phase II metabolic reaction was glucuronidation of hydroxyl benzyl metabolites of ponatinib. The major in vivo metabolic reactions were α hydroxylation and α oxidation at piperazine ring. Literature review revealed no articles that have been published on in vivo metabolism of ponatinib in Sprague Dawley rats or ponatinib in vivo phase I and phase II metabolites structural characterization and identification.
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http://dx.doi.org/10.1016/j.cca.2018.06.035DOI Listing
October 2018

The status of licensed pharmacy workforce in Saudi Arabia: a 2030 economic vision perspective.

Hum Resour Health 2018 06 28;16(1):28. Epub 2018 Jun 28.

College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Background: The economy of Saudi Arabia is currently undergoing a major transformation which will have an impact on employment in the pharmacy sector. However, quantitative data characterizing the pharmacy workforce in the Kingdom are currently not available. Therefore, the aim of this study was to determine the current status of the licensed pharmacy workforce in the pharmacy field in Saudi Arabia.

Methods: Descriptive statistics were performed on data from the Saudi Commission for Health Specialties (SCFHS) as of March 2017.

Results: The labor market for pharmacists in Saudi Arabia is dominated by expatriates. Saudi nationals constitute less than 20% of the pharmacists employed in the Kingdom. The underemployment of Saudis is most evident in the largest sectors of the pharmacy field, namely, private health care establishments, community pharmacies, and pharmaceutical companies.

Conclusion: There is an unmet need to train Saudi citizens as pharmacists and retain them in the workforce. Addressing this issue should become an important objective in Saudi Arabia's Vision for 2030.
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http://dx.doi.org/10.1186/s12960-018-0294-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022294PMC
June 2018

Effect of Naltrexone Hydrochloride on Cytochrome P450 1A2, 2C9, 2D6, and 3A4 Activity in Human Liver Microsomes.

Eur J Drug Metab Pharmacokinet 2018 Dec;43(6):707-713

Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.

Background And Objective: Cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 are the most important phase I drug-metabolizing enzymes in the liver, but there is a dearth of literature available on the effects of naltrexone hydrochloride on these major enzymes present in the human liver. Thus, in the present study, the effect of naltrexone hydrochloride on the activity of CYP1A2, 2C9, 2D6, and 3A4 using human liver microsomes (HLM) was investigated.

Methods: A selective probe for CYP1A2, 2C9, 2D6, and 3A4 was incubated with HLM with or without naltrexone hydrochloride. Phenacetin O-deethylation, tolbutamide 4-hydroxylation, dextromethorphan O-demethylation, and testosterone 6β-hydroxylation reactions were monitored for enzyme activity.

Results: The activity of all the studied CYP enzymes except 1A2 was significantly inhibited by naltrexone hydrochloride 1 µM. Furthermore, 1 µM naltrexone hydrochloride inhibited CYP3A4 enzyme activity, the most by 37.9% followed by CYP2C9 (36.5%) and CYP2D6 (31.8%). The CYP2C9 and CYP2D6 metabolic activities were greatly affected by naltrexone hydrochloride, which even at the lowest concentration of naltrexone hydrochloride (0.01 µM) significantly decreased the metabolic activity by 34.9 and 16.0%, respectively. The half maximal inhibition concentration (IC) values for CYP2C9 and CYP2D6 inhibition were 3.40 ± 1.78 and 5.92 ± 1.58 µM, respectively.

Conclusion: These outcomes advocate that there is a great possibility of drug interactions resulting from the concurrent administration of naltrexone hydrochloride with actives that are metabolized by these CYP enzymes, particularly CYP2C9 and CYP2D6. Nevertheless, further clarification is needed through detailed in vivo pharmacokinetic studies.
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http://dx.doi.org/10.1007/s13318-018-0482-xDOI Listing
December 2018
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