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Assessment of Apalutamide Metabolic Stability in HLMs Matrix Using a Sensitive and Fast UPLC-MS/MS Method: In Silico
Mohamed W Attwa1, Haitham AlRabiah1, Adnan A Kadi1
1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Biomedical Chromatography : BMC
|January 26, 2026
Summary
A new UPLC-MS/MS method accurately measures apalutamide (APD) metabolic stability in liver microsomes. This fast, sensitive, and green approach provides key insights into APD
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Analytical Chemistry
- Green Chemistry
Background:
- Apalutamide (APD) is an androgen receptor antagonist approved for prostate cancer.
- Understanding APD's metabolic stability is crucial for optimizing its therapeutic use.
- Existing methods for assessing metabolic stability may lack speed, sensitivity, or environmental sustainability.
Purpose of the Study:
- To develop and validate a rapid, sensitive, and environmentally friendly UPLC-MS/MS method for determining apalutamide metabolic stability in human liver microsomes (HLMs).
- To assess the greenness of the developed analytical method using in silico tools.
- To evaluate the metabolic lability of apalutamide using computational approaches.
Main Methods:
- Development of a UPLC-MS/MS assay using an isocratic mobile phase and a C18 column with baricitinib as the internal standard.
- Validation of the method for linearity, accuracy, and precision across a concentration range of 1.0 to 4000 ng/mL.
- In silico assessment of method greenness using AGREE and MoGAPI, and metabolic liability prediction using StarDrop (WhichP450 and DEREK modules).
Main Results:
- The UPLC-MS/MS method demonstrated high sensitivity, linearity, accuracy, and precision for APD quantification.
- The method is environmentally sustainable, utilizing a low percentage of acetonitrile, a low flow rate, and a short run time (1 minute).
- In vitro results indicated an APD half-life (t1/2) of 25.57 min and intrinsic clearance (Clint) of 31.7 mL/min/kg.
Conclusions:
- The developed UPLC-MS/MS method is a fast, reliable, sensitive, and green tool for assessing apalutamide metabolic stability in HLMs.
- In silico analysis suggests that modifications to the N-methyl moiety of APD could alter its metabolic stability, warranting further experimental investigation.
- This method supports further research into apalutamide's pharmacokinetic profile and the development of related drug candidates.
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