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Simultaneous quantitative analysis of letrozole, its carbinol metabolite, and carbinol glucuronide in human plasma by LC-MS/MS

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Abstract

Letrozole is an efficient endocrine treatment of postmenopausal breast cancer, however, not all patients benefit from this treatment, and moreover, severe side-effects like arthralgia frequently lead to discontinuation. To better understand inter-individual variability in drug response and side-effects, plasma analysis of steady-state concentrations of letrozole and its major metabolites is crucial. We developed a rapid, sensitive, and specific method for the simultaneous quantification of letrozole and its metabolites 4,4′-(hydroxymethylene)dibenzonitrile (carbinol) and bis(4-cyanophenyl)methyl hexopyranosiduronic acid (carbinol-gluc) by UHPLC-ESI-MS/MS using in-house synthesized, stable isotope-labeled internal standards. Following solid-phase extraction in BondElut C18 96-well plates, the analytes were separated on a ZORBAX Eclipse XDB-C18 column (1.8 μm, 4.6 × 50 mm) with a gradient of acetonitrile in 0.1% acetic acid in water and detected on a triple quadrupole mass spectrometer with electrospray ionization in the multiple reaction monitoring mode. Lower limits of quantification were 20, 0.2, and 2 nM for letrozole, carbinol, and carbinol-gluc, respectively. The assay has been validated according to FDA guidance and applied to the analysis of 20 plasma samples of postmenopausal breast cancer patients treated with 2.5 mg of letrozole per day. Mean plasma levels (±SD) were 366 ± 173, 0.38 ± 0.09, and 34 ± 12 nM for letrozole, carbinol, and carbinol-gluc, respectively. Our rapid and sensitive mass spectrometry based method enables future pharmacokinetic investigations of letrozole outcome.

LC-MS/MS analysis of letrozole and its metabolites in human plasma

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Acknowledgments

We thank the German Tamoxifen and AI clinicians group for recruiting letrozole-treated patients. This work was supported by grants from the Hans L. Merkle Foundation, the Robert Bosch Foundation (Stuttgart, Germany), and from the Federal Ministry for Education and Research (BMBF, Berlin, Germany; 03IS2061C and 01ZP0502).

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Authors and Affiliations

  1. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen, Auerbachstr. 112, 70376, Stuttgart, Germany

    Jana C. Precht, Boian Ganchev, Georg Heinkele, Hiltrud Brauch, Matthias Schwab & Thomas E. Mürdter

  2. Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology, University Hospital, Otfried-Müller-Straße 45, 72076, Tübingen, Germany

    Matthias Schwab

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  1. Jana C. Precht
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  2. Boian Ganchev
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  3. Georg Heinkele
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  4. Hiltrud Brauch
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  5. Matthias Schwab
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  6. Thomas E. Mürdter
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Correspondence to Thomas E. Mürdter.

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Precht, J.C., Ganchev, B., Heinkele, G. et al. Simultaneous quantitative analysis of letrozole, its carbinol metabolite, and carbinol glucuronide in human plasma by LC-MS/MS. Anal Bioanal Chem 403, 301–308 (2012). https://doi.org/10.1007/s00216-012-5813-1

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  • DOI: https://doi.org/10.1007/s00216-012-5813-1

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