Simultaneous determination of tolterodine and its two metabolites, 5-hydroxymethyltolterodine and N-dealkyltolterodine in human plasma using LC–MS/MS and its application to a pharmacokinetic study
2017
Kim, Yŏng-hun | Byeon, Ji-Yeong | Kim, Se-Hyung | Lee, Choong-Min | Jung, Eui Hyun | Chae, Won Ki | Jang, Choon-Gon | Lee, Seok-Yong | Lee, Yun Jeong
Tolterodine is a nonselective muscarinic antagonist that is indicated for the overactive urinary bladder and other urinary difficulties. We developed and validated a simple, rapid and sensitive high-performance liquid chromatography analytical method utilizing tandem mass spectrometry (LC–MS/MS) for the quantitation of tolterodine and its major metabolites, 5-hydroxymethyltolterodine (5-HMT) and N-dealkyltolterodine (NDT), in human plasma. After liquid–liquid extraction with methyl t-butyl ether, chromatographic separation of the three analytes was achieved using a reversed-phase Luna Phenyl-hexyl column (100 × 2.0 mm, 3 μm particles) with a mobile phase of 10 mM ammonium formate buffer (pH 3.5)-methanol (10:90, v/v) and quantified by MS/MS detection in electrospray ionization (ESI) positive ion mode. The retention time of tolterodine, 5-HMT, NDT, and internal standard (IS) were 1.4, 1.24, 1.33, and 1.26 min, respectively. The calibration curves were linear over a range of 0.025–10 ng/ml for tolterodine and 5-HMT, and 0.05–10 ng/ml for NDT. The lower limit of quantifications using 200 μl of human plasma was 0.025 ng/ml for tolterodine and 5-HMT, and 0.05 ng/ml for NDT. The mean accuracy and precision for intra- and inter-run validation of tolterodine, 5-HMT, and NDT were all within acceptable limits. These results showed that a simple, rapid and sensitive LC–MS/MS method for the quantification of tolterodine and its major metabolites in human plasma was developed. This method was successfully applied to a pharmacokinetic study in humans.
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