Palbociclib (Ibrance; Pfizer) was approved for the management of metastatic breast cancer characterized by hormone receptor‐positive/human epidermal growth factor receptor 2 negative status. The objective of this study was to create a fast, precise, environmentally friendly, and highly sensitive ultra‐high‐performance liquid chromatography‐tandem mass spectrometry approach for quantifying palbociclib (PAB) in human liver microsomes with the application for assessing metabolic stability. The validation features were performed in agreement with the bioanalytical method validation standards outlined by the US Food and Drug Administration. The StarDrop software (WhichP450 and DEREK modules) was used in screening the metabolic lability and structural alerts of PAB. The separation of PAB and encorafenib (as an internal standard) was achieved on a C8 column, employing an isocratic mobile phase. The inter‐day and intra‐day accuracy and precision ranged from ‐6.00% to 4.64% and from ‐2.33% to 3.13%, respectively. The constructed calibration curve displayed a linearity in the range of 1–3000 ng/mL. The sensitivity of the established approach was proven by the lower limit of quantification of 0.73 ng/mL. The Analytical GREEness calculator results revealed the high level of greenness of the developed method. The PAB's metabolic stability (t 1/2 of 18.5 min and a moderate clearance (Cl int ) of 44.8 mL/min/kg) suggests a high extraction ratio medication that matched the WhichP450 software results.

Palbociclib

10.1002/jssc.202400346

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Citations (4)

A new method to determine the new C-Met inhibitor “Cabozantinib” in dosage form and human plasma via micelle-enhanced spectrofluorimetry

RSC Advances (2015)

Hany W. Darwish Ali S. Abdelhameed Ahmed H. Bakheit Amer M. Alanazi

A highly sensitive and simple micelle-enhanced spectrofluorimetric method was developed for the determination of cabozantinib (CBZ) in its pharmaceutical formulation and spiked human plasma without any derivatization.

Cabozantinib

10.1039/c5ra04109k

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Citations (12)

A simple liquid chromatography-tandem mass spectrometry method to accurately determine the novel third-generation EGFR-TKI naquotinib with its applicability to metabolic stability assessment

RSC Advances (2019)

Haitham AlRabiah Adnan A. Kadi Mohamed W. Attwa Ali S. Abdelhameed

Naquotinib (ASP8273, NQT) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs). NQT was found to be more effective than osimertinib against the EGFR L858R plus T790M mutation (L858R+T790M). A rapid resolution liquid chromatography (RRLC)-tandem mass spectrometry (MS/MS) method was developed and validated for NQT quantification and its metabolic stability was investigated. NQT and foretinib (FTB) as an internal standard (IS) were separated using a mobile phase under isocratic conditions with a C18 column (reversed phase system). The linearity of the analytical method ranged from 5 to 500 ng mL-1 (coefficient of correlation [r2] ≥ 0.9999) in a human liver microsome (HLM) matrix. The limit of detection and limit of quantification were 0.78 and 2.36 ng mL-1, respectively. The inter-day and intra-day accuracy and precision were -6.36 to 1.88 and 0.99 to 2.58%, respectively. The metabolic stability of NQT in the HLM matrix was calculated using the in vitro half-life (t1/2, 67.96 min) and intrinsic clearance (Clint, 2.12 mL min-1 kg-1). NQT is considered to be a moderate extraction ratio drug that is moderately excreted from the human body compared with other related TKIs. This proposed methodology is thought to be the first method for assessing NQT concentration and its metabolic stability.

Osimertinib

Matrix (chemical analysis)

Coefficient of variation

Solid phase extraction

10.1039/c8ra09812c

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Citations (26)

Phase I metabolic profiling and unexpected reactive metabolites in human liver microsome incubations of X-376 using LC-MS/MS: bioactivation pathway elucidation andin silicotoxicity studies of its metabolites

RSC Advances (2020)

Mohamed W. Attwa Adnan A. Kadi Ali S. Abdelhameed

Metabolites ofX-376were characterized by LC-MS/MS. Pyridazine ring and dichloro-phenyl groups were bioactivated by novel pathways.

Metabolic pathway

Pyridazine

Human liver

Biotransformation

10.1039/c9ra09115g

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Citations (36)

A Comprehensive Spectroscopic and Computational Investigation to Probe the Interaction of Antineoplastic Drug Nordihydroguaiaretic Acid with Serum Albumins

PLoS ONE (2016)

Saima Nusrat Mohammad Khursheed Siddiqi Masihuz Zaman Nida Zaidi Mohammad Ajmal

Exogenous drugs that are used as antidote against chemotheray, inflammation or viral infection, gets absorbed and interacts reversibly to the major serum transport protein i.e. albumins, upon entering the circulatory system. To have a structural guideline in the rational drug designing and in the synthesis of drugs with greater efficacy, the binding mechanism of an antineoplastic and anti-inflammatory drug Nordihydroguaiaretic acid (NDGA) with human and bovine serum albumins (HSA & BSA) were examined by spectroscopic and computational methods. NDGA binds to site II of HSA with binding constant (Kb) ~105 M-1 and free energy (ΔG) ~ -7.5 kcal.mol-1. It also binds at site II of BSA but with lesser binding affinity (Kb) ~105 M-1 and ΔG ~ -6.5 kcal.mol-1. The negative value of ΔG, ΔH and ΔS for both the albumins at three different temperatures confirmed that the complex formation process between albumins and NDGA is spontaneous and exothermic. Furthermore, hydrogen bonds and hydrophobic interactions are the main forces involved in complex formation of NDGA with both the albumins as evaluated from fluorescence and molecular docking results. Binding of NDGA to both the albumins alter the conformation and causes minor change in the secondary structure of proteins as indicated by the CD spectra.

Nordihydroguaiaretic acid

Bovine serum albumin

Docking (animal)

Human serum albumin

10.1371/journal.pone.0158833

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Citations (76)

An asymmetric and slightly dimerized structure for the tetanus toxoid protein used in glycoconjugate vaccines

Carbohydrate Polymers (2012)

Ali S. Abdelhameed Gordon A. Morris Gary G. Adams Arthur J. Rowe Olivier Laloux

Toxoid

Sedimentation equilibrium

Glycoconjugate

Sedimentation

Trimer

Globular protein

10.1016/j.carbpol.2012.07.032

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Citations (21)

An UPLC–ESI–MS/MS Bioanalytical Methodology for the Quantification of Gilteritinib in Human Liver Microsomes: Application to In Vitro and In Silico Metabolic Stability Estimation

Separations (2023)

Mohamed W. Attwa Haitham AlRabiah Aishah M. Alsibaee Ali S. Abdelhameed Adnan A. Kadi

Gilteritinib (Xospata®) is a tyrosine kinase inhibitor (TKI) that works by inhibiting numerous receptor tyrosine kinases, involving AXL and FMS-like tyrosine kinase 3 (FLT3). Gilteritinib (GTB) was approved (28 November 2018) by the USFDA for the treatment of refractory or relapsed (R/R) acute myeloid leukemia (AML) with a FLT3 mutation. In the current study, a fast, highly sensitive, and specific ultra-performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) analytical methodology was created for GTB determination in human liver microsomes (HLMs) utilizing an electrospray ionization (ESI) source. The developed methodology (UPLC–ESI–MS/MS) was utilized in the assessment of GTB metabolic stability. The UPLC–ESI–MS/MS methodology was validated following the rules of the FDA that include selectivity, linearity, accuracy, precision, matrix effect, stability, and extraction recovery. The generated data of the optimized validation parameters of the current UPLC–ESI–MS/MS methodology were acceptable as reported in the FDA guidelines. GTB parent ions were generated in the ESI source (positive mode) and GTB daughter ions (two) were quantified in the mass analyzer utilizing multiple reaction monitoring (MRM) modes. The plotted GTB calibration curve showed a wide range of linearity from 1 ng/mL to 3000 ng/mL in HLMs matrix (y = 1.7298x + 3.62941 and r2 = 0.9949). The intraday and interday precision and accuracy outcomes of the current UPLC–ESI–MS/MS methodology were 0.35–11.39% and 0.27–4.32%, respectively. GTB and encorafenib (EFB) (internal standard; IS) were resoluted utilizing a reversed stationary phase (ZORBAX Eclipse plus C18 column; 1.8 μm PS, 2.1 mm ID, and 50 mm L) at 22 ± 2 °C. The calculated lower limit of quantification (LLOQ) was 0.94 ng/mL, revealing the UPLC–ESI–MS/MS methodology sensitivity. The two metabolic stability factors including in vitro half-life (t1/2) and intrinsic clearance (Clint) of GTB were 14.32 min and 56.64 mL/min/kg, respectively, predicting the moderate extraction ratio and good bioavailability of GTB. The current UPLC–ESI–MS/MS methodology is fast, sensitive and exhibits a wider range of linearity (1 to 3000 ng/mL) compared to other reported methods and is considered the first validated methodology for the determination of GTB metabolic stability.

Bioanalysis

10.3390/separations10050278

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Citations (13)

Change in Nfkb/Nrf2/Bax Levels by High Monomeric Polyphenols Berries Extract (HMPBE) in Acute and Chronic Secondary Brain Damage

Cellular Physiology and Biochemistry (2024)

Sergio Modafferi Francesco Molinari Livia Interdonato Roberta Fusco Daniela Impellizzeri

Background/Aims: High Monomeric Polyphenols Berries Extract (HMPBE) is a formula highly rich in polyphenols clinically proven to enhance learning and memory. It is currently used to enhances cognitive performance including accuracy, working memory and concentration. Methods: Here, we investigated for the first time the beneficial effects of HMPBE in a mouse model of acute and chronic traumatic brain injury (TBI). Results: HMPBE, at the dose of 15 mg/kg was able to reduce histological alteration as well as inflammation and lipid peroxidation. HMPBE ameliorate TBI by improving Nrf-2 pathway, reducing Nf-kb nuclear translocation and apoptosis, and ameliorating behavioral alteration such as anxiety and depression. Moreover, in the chronic model of TBI, HMPBE administration restored the decline of Tyrosine Hydroxylase (TH) and dopamine transporter (DAT) and the accumulation of a-synuclein into the midbrain region. This finding correlates the beneficial effect of HMPBE administration with the onset of parkinsonism related to traumatic brain damage. Conclusion: The data may open a window for developing new support strategies to limit the neuroinflammation event of acute and chronic TBI.

10.33594/000000731

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Assessment of the in vitro metabolic stability of CEP-37440, a selective FAK/ALK inhibitor, in HLMs using fast UPLC–MS/MS method: in silico metabolic lability and DEREK alerts screening

Frontiers in Chemistry (2024)

Mohamed W. Attwa Haitham AlRabiah Ali S. Abdelhameed Adnan A. Kadi

CEP-37440 was synthesized and supplied by the research and development division of Teva Branded Pharmaceutical Products (West Chester, PA, United States). CEP-37440 represents a newly developed compound that exhibits selectivity inhibition of Focal Adhesion Kinase and Anaplastic Lymphoma Kinase FAK/ALK receptors, demonstrating novel characteristics as an orally active inhibitor. The simultaneous inhibition of ALK and FAK can effectively address resistance and enhance the therapeutic efficacy against tumors through a synergistic mechanism.

Lability

Metabolic stability

10.3389/fchem.2024.1323738

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Citations (0)