Ultra-Fast Green UPLC-MS/MS Method for the Quantification of Cediranib in the Human Liver Microsome Matrix: In Vitro and In Silico Metabolic Stability Assessment
Mohamed W. Attwa, Ali S. Abdelhameed, Adnan A. Kadi
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引用次数: 0
Abstract
Cediranib (AZD2171; CDB) is an oral pan-VEGF receptor tyrosine kinase inhibitor and a potent antiangiogenic agent. This study sought to develop a precise, rapid, dependable, and sustainable UPLC-MS/MS approach for measuring CDB in the human liver microsome (HLM) matrix, utilized for assessing the CDB metabolic stability inside this matrix. The validation processes for the UPLC-MS/MS system adhered to US-FDA rules for bioanalytical technique validation. The validated method utilized the HLM matrix throughout a level range of 1–4000 ng/mL with a duration of 1 min on UPLC-MS/MS instrumentation. The precision (%RSD) and accuracy (%E) rates for intraday and interday measurements varied from −1.41% to 8.0% and from −2.75% to 9.67%, respectively. The StarDrop software employed P450 and DEREK modules to evaluate metabolic lability and to characterize CDB structural warnings, respectively. The in vitro t1/2 was determined to be 25.48 min, and the CDB intrinsic clearance was determined to be 31.82 mL/min/kg. In silico assessments indicate that slight structural modifications to the pyrrolidine moiety (61%), methyl group (32%), and the propyl group (7%) in drug design could increase the CDB metabolic stability. The assessment of in silico CDB ADME characteristics and metabolic stability is fundamental for progressing innovative drug research focused on augmenting metabolic stability.
期刊介绍:
Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.