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Simultaneous quantification of the CYP2D6 substrate yohimbine, its metabolite 11-OH-yohimbine, and the CYP2D6 inhibitor paroxetine in human plasma

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Abstract

We developed and validated a human plasma LC-MS/MS assay according to FDA guidelines to determine the impact of the CYP2D6 inhibitor paroxetine on the pharmacokinetics of the assumed specific CYP2D6 substrate yohimbine. Yohimbine, its main metabolite 11-OH-yohimbine, and paroxetine were quantified using plasma (100 μL) and liquid–liquid extraction for sample preparation. Analytes were separated with a Phenomenex Luna C18 3 μm LC column using a gradient consisting of ammonium acetate (5 mM), acetic acid, and acetonitrile. Tandem mass spectrometry detection was performed using positive electrospray ionization and selective reaction monitoring utilizing 13C- and deuterium-labeled internal standards in the calibration range from 0.5 to 500 ng mL−1. Accuracy at the lower limit of quantification of 0.5 ng mL−1 was <19% with the corresponding precision being <16%. Within-batch and batch-to-batch accuracies were <14% with the corresponding precision being <12%. Extraction recoveries ranged between 75 and 113% for all analytes. This assay was used to simultaneously quantify plasma concentrations of yohimbine, its metabolite, and paroxetine after oral administration of 5 mg yohimbine solely and in combination with a three-day intake of 20 mg paroxetine to a healthy individual. This enabled the investigation of yohimbine pharmacokinetics and its CYP2D6 dependent metabolization in correlation with plasma exposure to the CYP2D6 inhibitor paroxetine, resulting in doubled maximum concentration, a tenfold increase of AUC and fourfold prolonged elimination half-life.

Graphical abstract: Simultaneous quantification of the CYP2D6 substrate yohimbine, its metabolite 11-OH-yohimbine, and the CYP2D6 inhibitor paroxetine in human plasma

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Publication details

The article was received on 09 Aug 2019, accepted on 01 Nov 2019 and first published on 04 Nov 2019


Article type: Paper
DOI: 10.1039/C9AY01715A
Anal. Methods, 2019, Advance Article

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    Simultaneous quantification of the CYP2D6 substrate yohimbine, its metabolite 11-OH-yohimbine, and the CYP2D6 inhibitor paroxetine in human plasma

    M. Vay, G. Skopp, G. Mikus and J. Burhenne, Anal. Methods, 2019, Advance Article , DOI: 10.1039/C9AY01715A

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