A simultaneous determination method for 5‐fluorouracil and its metabolites in human plasma with linear range adjusted by in‐source collision‐induced dissociation using hydrophilic interaction liquid chromatography–electrospray ionization–tandem mass spectrometry

Abstract

We applied a new technique for quantitative linear range shift using in-source collision-induced dissociation (CID) to complex biological fluids to demonstrate its utility. The technique was used in a simultaneous quantitative determination method of 5-fluorouracil (5-FU), an anticancer drug for various solid tumors, and its metabolites in human plasma by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS). To control adverse effects after administration of 5-FU, it is important to monitor the plasma concentration of 5-FU and its metabolites; however, no simultaneous determination method has yet been reported because of vastly different physical and chemical properties of compounds. We developed a new analytical method for simultaneously determining 5-FU and its metabolites in human plasma by LC/ESI-MS/MS coupled with the technique for quantitative linear range shift using in-source CID. Hydrophilic interaction liquid chromatography using a stationary phase with zwitterionic functional groups, phosphorylcholine, was suitable for separation of 5-FU from its nucleoside and interfering endogenous materials. The addition of glycerin into acetonitrile-rich eluent after LC separation improved the ESI-MS response of high polar analytes. Based on the validation results, linear range shifts by in-source CID is the reliable technique even with complex biological samples such as plasma. Copyright © 2016 John Wiley & Sons Ltd.

Simultaneous analysis of oral anticancer drugs for renal cell carcinoma in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry

“…We hypothesized that the nonlinearity of the calibration curve was due to saturation of the electron multiplier in the detector, and that reducing the amount of ions introduced into the mass spectrometer would be an effective solution. Utilization of in‐source CID has been found to be useful for controlling the linear range of quantification in this manner (Ishii, Shimada, et al, ; Ishii, Yamaguchi, & Mano, ; Ishii et al, ). We therefore investigated the MS conditions that cause moderate in‐source CID, and achieved linearity within the target range for sorafenib and pazopanib, as shown in Table .…”

“…However, the therapeutic windows of those four TKIs are different from each other (Faivre et al, ; Fukudo et al, ; Kato et al, ; Noda et al, ; Shimada et al, ; Suttle et al, ), and it is difficult to measure their plasma concentrations under the same conditions using LC/ESI‐MS/MS. Recently, we have demonstrated the usefulness of a linear range‐shifting technique using in‐source collision‐induced dissociation (CID), and shown that this technique is capable of analyzing the concentrations of a drug and its metabolites in human plasma simultaneously (Ishii, Shimada, et al, ; Ishii, Yamaguchi, & Mano, ; Ishii et al, ).…”

In‐source collision‐induced dissociation (IS‐CID): Applications, issues and structure elucidation with single‐stage mass analyzers

“…Quantitation based on the sums of peak area resulted in high sensitivity. Other researchers have used the low abundance IS‐CID ions to increase the linear dynamic range of MS systems at the expense of sensitivity.…”

Antineoplastic drugs and their analysis: a state of the art review

“…64 94,95 or the use of normal phase chromatographic supports. [96][97][98][99] However, all of these approaches suffer from obvious limitations, including long column equilibration, poor kinetic performance, tedious sample preparation procedures, or incompatibility with MS. More recently, hydrophilic interaction chromatography (HILIC) has been proposed as an alternative strategy for the analysis of 5FU 100,101,102 and cytidine analogues 103,104 as shown in Fig. 3.…”