Development of a Highly Sensitive Methodology for Quantitative Determination of Fexofenadine in a Microdose Study by Multiple Injection Method Using Ultra-High Performance Liquid Chromatography with Tandem Mass Spectrometry

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  • Tanaka Yukari
    Drug Metabolism and Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd. Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry, Kyoto Pharmaceutical University
  • Yoshikawa Yutaka
    Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry, Kyoto Pharmaceutical University
  • Yasui Hiroyuki
    Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry, Kyoto Pharmaceutical University

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An ultra high-sensitivity method for quantifying fexofenadine concentration in rat plasma samples by multiple injection method (MIM) was developed for a microdose study. In this study, MIM involved continuous injections of multiple samples containing the single compound into a column of the ultra-HPLC (UHPLC) system, and then, temporary trapping of the analyte at the column head. This was followed by elution of the compound from the column and detection by mass spectrometer. Fexofenadine, used as a model compound in this study, was extracted from the plasma samples by a protein precipitation method. Chromatographic separation was achieved on a reversed-phase C18 column by using a gradient method with 0.1% formic acid and 0.1% formic acid in acetonitrile as the mobile phase. The analyte was quantified in the positive-ion electrospray ionization mode using selected reaction monitoring. In this study, the analytical time per fexofenadine sample was approximately 2 min according to the UHPLC system. The method exhibited the linear dynamic ranges of 5–5000 pg/mL for fexofenadine in rat plasma. The intra-day precisions were from 3.2 to 8.7% and the accuracy range was 95.2–99.3%. The inter-day precisions and accuracies ranged from 3.5 to 8.4% and from 98.6 to 102.6%, respectively. The validated MIM was successfully applied to a microdose study in the rats that received oral administration of 100 µg/kg fexofenadine. We suggest that this method might be beneficial for the quantification of fexofenadine concentrations in a microdose clinical study.

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