LAUSR.org creates dashboard-style pages of related content for over 1.5 million academic articles. Sign Up to like articles & get recommendations!

Analytical aspects of sunitinib and its geometric isomerism towards therapeutic drug monitoring in clinical routine

Photo by karsten116 from unsplash

HIGHLIGHTSSunitinib is a tyrosine kinase inhibitor and a candidate for TDM approach.Sunitinib and N‐desethyl sunitinib undergo light‐induced Z/E isomerization.Sample handling/analysis require light protection to preserve the active Z‐form.A fast and… Click to show full abstract

HIGHLIGHTSSunitinib is a tyrosine kinase inhibitor and a candidate for TDM approach.Sunitinib and N‐desethyl sunitinib undergo light‐induced Z/E isomerization.Sample handling/analysis require light protection to preserve the active Z‐form.A fast and quantitative reconversion of the E‐ to Z‐isomer is possible.The simple additional step allows to develop a method suitable to clinical routine. ABSTRACT Sunitinib malate, an oral multi‐targeted tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma, gastrointestinal stromal tumor, and well‐differentiated pancreatic neuroendocrine tumors, has been identified as a potential candidate for therapeutic drug monitoring approach. Nevertheless, the development of an analytical assay suitable for clinical application for the quantification of the plasma concentration of sunitinib and its active metabolite, N‐desethyl sunitinib, is limited by its Z/E isomerization when exposed to light. Several LC–MS/MS methods already published require protection from light during all sample handling procedures to avoid the formation of E‐isomer, which makes them not suitable for clinical practice. In order to obtain a simple and fast procedure to reconvert the E‐isomer, formed during sample collection and treatment without light protection, and, thus, to have only Z‐isomer peak to quantify, we studied the Z/E photodegradation with special attention to the condition allowing the reverse reaction in plasma matrix. After 30 min of light exposure, the E‐isomer maximum percentage of both the analytes was reached (44% of E‐sunitinib and 20% of E‐N‐desethyl sunitinib; these percentages were calculated with respect to the sum of E + Z). Moreover, the formation of the E‐isomer increased up to 20% after lowering the pH of the solution. Since the reverse reaction takes place when the pre‐exposed solution is placed in dark, we followed the E to Z‐isomer kinetics into the autosampler. The conversion rate was very slow when the autosampler was set at 4 °C (after 4 h the mean percentages of E‐isomer were 50% for sunitinib and 22% for N‐desethyl sunitinib). The reconversion rate was considerably accelerated with the increasing of the temperature: incubating the analytical solution in a heated water bath for 5 min at 70 °C we obtained the quantitative (99%) reconversion of the E‐ to the Z‐isomer. No effect of concentration was observed, while the presence of acids inhibited the reconversion. Based on these results, a simple and fast procedure was setup to quantitatively reconvert the E‐isomer formed during sample collection and processing without light protection into its Z‐form thus leading to a single peak to quantify. The application of this additional step allows to develop a LC–MS/MS method suitable to clinical practice, due to its practicality and speed.

Keywords: isomer; clinical routine; sunitinib; therapeutic drug; suitable clinical; desethyl sunitinib

Journal Title: Journal of Pharmaceutical and Biomedical Analysis
Year Published: 2018

Link to full text (if available)


Share on Social Media:                               Sign Up to like & get
recommendations!

Related content

More Information              News              Social Media              Video              Recommended



                Click one of the above tabs to view related content.