Details

Autor(en) / Beteiligte

• Sikkema, Barend J.
• Mathijssen, Ron H.J.
• Robbrecht, Debbie G.J.
• Perera, Timothy P.S.
• Koolen, Stijn L.W.
• de Bruijn, Peter

Titel

Quantification and clinical validation of the selective MET kinase inhibitor DO-2 and its metabolites DO-5 and M3 in human plasma

Ist Teil von

• Journal of pharmaceutical and biomedical analysis, 2024-03, Vol.240, p.115962, Article 115962

Ort / Verlag

England: Elsevier B.V

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• DO-2 is a highly selective MNNG HOS transforming (MET) inhibitor. This deuterated drug is thought to diminish the formation of the Aldehyde Oxidase 1 inactive metabolite M3. For various reasons, quantification of DO-2 and its metabolites M3 and DO-5 is highly relevant. In this study, we present an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to quantify DO-2, M3 and DO-5. Rolipram served as the internal standard. Aliquots of 25 µL were mixed with 100 µL internal standard consisting of 10 ng/mL rolipram in acetonitrile. Separation of the analytes was achieved on an Acquity UPLC ® HSS T3 column, utilizing gradient elution with water/formic acid and acetonitrile/formic acid at a flow-rate of 0.400 mL/min. Calibration curves were linear in the range of 1.00 – 1000 ng/mL for DO-2 and DO-5, and 2.00 – 2000 ng/mL for M3 in human plasma. The within-run and between-run precisions of DO-2, DO-5 and M3, also at the level of the LLQ, were within 12.1%, while the accuracy ranged from 89.5 to 108.7%. All values for accuracy, within-run and between-run precisions met the criteria set by the Food and Drug Administration. The method was effectively employed in the analysis of samples obtained from a clinical trial. [Display omitted] •We describe the first UPLC-MS/MS method for the analysis of DO-2 and its metabolites DO-5 and M3 in human plasma.•The assay met all of the current requirements of bioanalytical method validation.•Clinical applicability of the assay was demonstrated for pharmacokinetic analysis in clinical pharmacokinetic studies.