Eco-Friendly, Simple, Fast, and Sensitive UPLC-MS/MS Method for Determination of Pexidartinib in Plasma and Its Application to Metabolic Stability

Ezzeldin, Essam; Iqbal, Muzaffar; Asiri, Yousif A.; Mostafa, Gamal A. E.; Sayed, Ahmed Y A

doi:10.3390/molecules27010297

Cited by 2 publications

(1 citation statement)

References 25 publications

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“…Because of its intrinsic simplicity, this specific model is frequently used in studies pertaining to drug metabolism. According to earlier research [16][17][18][19], the ACB showed a moderate metabolism rate, which led to a favorable in vivo bioavailability and a moderate duration of action. The small extraction ratio of ACB was discovered to be in line with the frequently advised regular dosage of ACB (100 mg), which should be given twice daily to patients diagnosed with B-cell malignancies [20].…”

Section: Introductionmentioning

confidence: 98%

An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib

Attwa,

Bakheit,

Abdelhameed

et al. 2023

Molecules

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Acalabrutinib, commercially known as Calquence®, is a pharmacological molecule that has robust inhibitory activity against Bruton tyrosine kinase. The medicine in question was carefully developed by the esteemed pharmaceutical company AstraZeneca. The FDA granted authorization on 21 November 2019 for the utilization of acalabrutinib (ACB) in the treatment of small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) in adult patients. The aim of this study was to develop a UPLC–MS/MS method that is effective, accurate, environmentally sustainable, and has a high degree of sensitivity. The methodology was specifically developed with the intention of quantifying ACB in human liver microsomes (HLMs). The methodology described above was subsequently utilized to assess the metabolic stability of ACB in HLMs in an in vitro environment. The validation procedures for the UPLC–MS/MS method in the HLMs were conducted in accordance with the bioanalytical method validation criteria established by the U.S.- DA. The utilization of the StarDrop software (version 6.6), which integrates the P450 metabolic module and DEREK software (KB 2018 1.1), was employed for the purpose of evaluating the metabolic stability and identifying potential hazardous alarms associated with the chemical structure of ACB. The calibration curve, as established by the ACB, demonstrated a linear correlation across the concentration range of 1 to 3000 ng/mL in the matrix of HLMs. The present study conducted an assessment of the accuracy and precision of the UPLC–MS/MS method in quantifying inter-day and intra-day fluctuations. The inter-day accuracy demonstrated a spectrum of values ranging from −1.00% to 8.36%, whilst the intra-day accuracy presented a range of values spanning from −2.87% to 4.11%. The t1/2 and intrinsic clearance (Clint) of ACB were determined through in vitro testing to be 20.45 min and 39.65 mL/min/kg, respectively. The analysis concluded that the extraction ratio of ACB demonstrated a moderate level, thus supporting the recommended dosage of ACB (100 mg) to be administered twice daily for the therapeutic treatment of persons suffering from B-cell malignancies. Several computational tools have suggested that introducing minor structural alterations to the butynoyl group, particularly the alpha, beta-unsaturated amide moiety, or substituting this group during the drug design procedure, could potentially enhance the metabolic stability and safety properties of novel derivatives in comparison to ACB.

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Section: Introductionmentioning

confidence: 98%

An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib

Attwa,

Bakheit,

Abdelhameed

et al. 2023

Molecules

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Quantitative Determination of 5-Aminoisoquinoline, a PARP-1 Inhibitor by UPLC-MS/MS: In Silico ADME Profile and In Vitro Metabolic Stability Study

et al. 2022

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5-Aminoisoquinoline (5-AIQ) is a water-soluble, potent and selective Poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor, widely used as a biochemical and pharmacological tool to study the inhibitory effect of PARPs enzyme. In this study, a simple, selective and reliable ultra-performance liquid chromatography-tandem mass spectrometry assay has been developed for the quantitative analysis of 5-AIQ in plasma using pantoprazole as an internal standard (IS). Both 5-AIQ and IS were separated on an Acquity CSH18 (2.1 × 100 mm; 1.7 µm) column after chromatographic elution of mobile phase comprising of 10 mM ammonium acetate and acetonitrile (35:65; v/v) at a flow rate of 0.3 mL/min. Electrospray ionization in positive mode was used for sample ionization and precursor to product ion transitions of 145.0 > 91.0; 145.0 > 117.4 for 5-AIQ and 384.0 > 138.1 for IS were used for detection and quantification in multiple reaction monitoring mode. The assay was linear in the concentration range of 1.0 to 666 ng/mL with correlation coefficient of ≥0.995. The precision and bias were within the acceptable limits of ≤12.68% and −8.6 to 5.9%, respectively, with mean recovery of 79.1% from plasma and negligible matrix effects (92.4%). In silico ADME prediction, 5-AIQ showed to be very soluble in water and high gastrointestinal absorption along with blood–brain barrier (BBB) permeability. The validated assay was successfully applied in a metabolic stability study, and 5-AIQ was moderately metabolized by human liver microsomes with an in vitro half-life of 14.5 min and intrinsic clearance of 47.6 µL/min/mg. The validated method can be utilized for future pharmacokinetic and bio-distribution studies.

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Eco-Friendly, Simple, Fast, and Sensitive UPLC-MS/MS Method for Determination of Pexidartinib in Plasma and Its Application to Metabolic Stability

Cited by 2 publications

References 25 publications

An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib

An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib

Quantitative Determination of 5-Aminoisoquinoline, a PARP-1 Inhibitor by UPLC-MS/MS: In Silico ADME Profile and In Vitro Metabolic Stability Study

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