Validated liquid chromatography tandem mass spectrometry for simultaneous quantification of foretinib and lapatinib, and application to metabolic stability investigation

Alanazi, Mohammed M.; Alkahtani, Hamad M.; Almehizia, Abdulrahman A.; Attwa, Mohamed W.; Bakheit, Ahmed H.; Darwish, Hany W.

doi:10.1039/c9ra03251g

Cited by 12 publications

(4 citation statements)

References 20 publications

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“…So as to determine the metabolic stability of NZT, the researchers gathered data pertaining to the reactivity of specific atoms, which was subsequently employed to establish the CSL value. Then, this number was employed to acquire comprehension about the metabolic reactivity of NZT [ 39 , 40 ]. The CSL was computed utilizing Equation (1) .…”

Section: Methodsmentioning

confidence: 99%

Characterization of the in vitro metabolic profile of nazartinib in HLMs using UPLC-MS/MS method: In silico metabolic lability and DEREK structural alerts screening using StarDrop software

Attwa,

Abdelhameed,

Kadi

2024

Heliyon

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Section: Methodsmentioning

confidence: 99%

Characterization of the in vitro metabolic profile of nazartinib in HLMs using UPLC-MS/MS method: In silico metabolic lability and DEREK structural alerts screening using StarDrop software

Attwa,

Abdelhameed,

Kadi

2024

Heliyon

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“…The validation of the established methodology was verified by calculating various analytical parameters. The details of the parameters were the same as those published in our previous work [34,35].…”

Section: Methods Validationmentioning

confidence: 99%

An LC–MS/MS Analytical Method for Quantifying Tepotinib in Human Liver Microsomes: Application to In Vitro and In Silico Metabolic Stability Estimation

et al. 2023

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Tepotinib (MSC2156119) is a potent mesenchymal–epithelial transition (MET) factor inhibitor, a receptor tyrosine kinase that plays a crucial role in promoting cancer cell malignant progression. Adverse effects of tepotinib (TEP), such as peripheral edema, interstitial lung disease, nausea and diarrhea, occur due to drug accumulation and lead to termination of therapy. Therefore, the in silico and experimental metabolic susceptibility of TEP was investigated. In the current work, an LC-MS/MS analytical method was developed for TEP estimation with metabolic stability assessment. TEP and lapatinib (LTP) used as internal standards (ISs) were separated on a reversed-phase C18 column using the isocratic mobile phase. Protein precipitation steps were used to extract TEP from the human liver microsome (HLM) matrix. An electrospray ionization multi-reaction monitoring (MRM) acquisition was conducted at m/z 493→112 for TEP, at m/z 581→350, and 581→365 for the IS. Calibration was in the range of 5 to 500 ng/mL (R2 = 0.999). The limit of detection (LOD) was 0.4759 ng/mL, whereas the limit of quantification (LOQ) was 1.4421 ng/mL. The reproducibility of the developed analytical method (inter- and intra-day precision and accuracy) was within 4.39%. The metabolic stability of TEP in HLM was successfully assessed using the LC-MS/MS method. The metabolic stability assessment of TEP showed intermediate Clint (35.79 mL/min/kg) and a moderate in vitro t1/2 (22.65 min), proposing the good bioavailability and moderate extraction ratio of TEP. The in silico results revealed that the N-methyl piperidine group is the main reason of TEP metabolic lability. The in silico Star Drop software program could be used in an effective protocol to confirm and propose the practical in vitro metabolic experiments to spare resources and time, especially during the first stages for designing new drugs. The established analytical method is considered the first LC-MS/MS method for TEP estimation in the HLM matrix with its application to metabolic stability assessment.

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“…The regression equation for the linear part of the curve was y = −0.0096x + 4.6022 with r 2 = 0.9833 that was used for in vitro t 1/2 calculation (Table 5). [22][23][24][25] Using the next equations: In vitro t 1/2 and Cl int were 72.7 min and 9.59 µL/min/ mg, respectively.…”

Section: Metabolic Stabilitymentioning

confidence: 99%

<p>Metabolic Stability Assessment of New PARP Inhibitor Talazoparib Using Validated LC–MS/MS Methodology: In silico Metabolic Vulnerability and Toxicity Studies</p>

Attwa¹,

Kadi²,

Alhazmi³

2020

DDDT

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Background: Talazoparib (BMN673) is a new poly(ADP-ribose) polymerase inhibitor that has been FDA approved for patients suffering from metastatic breast cancer with germline BRCA mutations. Method and Results: In the current study, an accurate and efficient liquid chromatographytandem mass spectrometry (LC-MS/MS) analytical methodology was developed for TZB estimation in addition to its metabolic stability assessment. TZB and lapatinib (LAP) (which is chosen as an internal standard; IS) were separated using reversed phase elution system (Hypersil C 18 column) with an isocratic mobile phase. The linearity range of the established method was 5-500 ng/mL (r 2 ≥ 0.999) in the human liver microsomes (HLMs) matrix. Different parameters were calculated to confirm the method sensitivity (limit of quantification was 2.0 ng/mL), and reproducibility (intra-and inter-day precision and accuracy were below 3.1%) of our methodology. For evaluation of TZB metabolic stability in HLM matrix, intrinsic clearance (9.59 µL/min/mg) and in vitro half-life (72.7 mins) were calculated. TZB treatment discontinuations were reported due to adverse events and dose accumulation, so in silico metabolic vulnerability (experimental and in silico) and toxicity assessment (in silico) of TZB were performed utilizing P450 Metabolism and DEREK modules of StarDrop software. Conclusion: TZB is slowly metabolized by the liver. TZB was reported to be minimally metabolized by the liver that approved our outcomes. We do recommend that plasma levels be monitored in cases when talazoparib is used for a long period of time, since it is possible for TZB to bioaccumulate after multiple doses to toxic levels. According to our knowledge, the current method is considered the first LC-MS/MS methodology for evaluating TZB metabolic stability. Further drug discovery studies can be done depending on this concept allowing the designing of new series of compounds with more safety profile through reducing side effects and improving metabolic behavior.

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Validated liquid chromatography tandem mass spectrometry for simultaneous quantification of foretinib and lapatinib, and application to metabolic stability investigation

Abstract: Foretinib metabolic rate is decreased in combination with lapatinib. Lapatinib metabolic rate is greatly increased in combination with foretinib. Dose recalculation should be considered when foretinib and lapatinib are used in combination.

Cited by 12 publications

References 20 publications

Characterization of the in vitro metabolic profile of nazartinib in HLMs using UPLC-MS/MS method: In silico metabolic lability and DEREK structural alerts screening using StarDrop software

Characterization of the in vitro metabolic profile of nazartinib in HLMs using UPLC-MS/MS method: In silico metabolic lability and DEREK structural alerts screening using StarDrop software

An LC–MS/MS Analytical Method for Quantifying Tepotinib in Human Liver Microsomes: Application to In Vitro and In Silico Metabolic Stability Estimation

<p>Metabolic Stability Assessment of New PARP Inhibitor Talazoparib Using Validated LC–MS/MS Methodology: In silico Metabolic Vulnerability and Toxicity Studies</p>

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