Exploring the metabolic characteristics and pharmacokinetic variation of paroxetine in healthy volunteers using a pharmacometabonomic approach.

The pharmacokinetic parameters of paroxetine vary between individuals, leading to differences in efficacy. The focus of our research was to predict responses to paroxetine using a pharmacometabonomic approach combining metabolic phenotypes and pharmacokinetic parameters. The pharmacokinetics of 12 healthy volunteers treated with paroxetine over two cycles was determined using high-performance liquid chromatography tandem mass spectrometry. Metabolic profiling and phenotyping were performed on the blood samples that remained after pharmacokinetic studies, using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry. Thirty-nine metabolites (p < 0.05) increased or decreased after treatment with paroxetine. Vitamin B6 metabolism; valine, leucine, and isoleucine biosynthesis; phenylalanine metabolism; pantothenate and coenzyme A biosynthesis; tyrosine metabolism; and glyoxylate and dicarboxylate metabolism were likely to be relevant for the effects of paroxetine. The two-stage partial least squares (PLS) strategy was used to screen potential biomarkers and predict the pharmacokinetic parameters of paroxetine. An orthogonal PLS discriminant analysis strategy was then applied to separate the high- and low-value groups based on the screened biomarkers. Pearson correlation test and receiver operating characteristic curve analysis confirmed the key prediction biomarkers. Seven common biomarkers were able to predict both the area under the curve (AUC) and the maximum concentration (Cmax ): cortisone, l-tyrosine, phenylpyruvate, l-valine, 2-oxoglutarate, l-lactate, and glycerate. Furthermore, homoprotocatechuate and l-glutamate were unique biomarkers for AUC, and citicoline and fumarate were unique biomarkers for Cmax . The selected biomarkers were able to predict the AUC and Cmax and discriminate good responders from poor responders to paroxetine treatment. This trial was registered with https://www.chinadrugtrials.org.cn/ (no. CTR20171590).