1. Predicting Pharmacokinetics Variation of Faropenem Using a Pharmacometabonomic Approach.
- Author
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Xing X, Ma P, Huang Q, Qi X, Zou B, Wei J, Tao L, Li L, Zhou G, and Song Q
- Subjects
- Animals, Chromatography, High Pressure Liquid, Chromatography, Liquid, Rats, beta-Lactams, Metabolomics, Tandem Mass Spectrometry
- Abstract
Individual variation in pharmacokinetics of faropenem is significant. We attempted to predict drug response of faropenem using a pharmacometabonomic approach. Metabolic profiling was performed on predose plasma samples from 36 healthy volunteers by gas chromatography-mass spectrometry (GC/MS), with 204 endogenous metabolites detected. Plasma concentration was measured after drug administration, using high pressure liquid chromatography-tandem mass spectroscopy (LC/MS/MS), and the pharmacokinetic parameters were calculated. Then a two-stage partial least squares strategy was employed to screen potential biomarkers and predict the pharmacokinetic parameters of faropenem. The results showed a good prediction of AUC and C
max with the screened biomarkers, and metabolites such as valine, proline, aspartic acid, gluconic acid, glucuronic acid, and 2-ketoisocaproic acid were indicated as candidate biomarkers. Finally, we explored the mechanism of individual variation by pathway enrichment analysis, and it suggested that organic anion transporter 1 (OAT1) and 3 (OAT3) might be responsible for individual variation of faropenem, and this hypothesis was verified by an experiment in rats.- Published
- 2020
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