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Predicting Pharmacokinetics Variation of Faropenem Using a Pharmacometabonomic Approach
Xiaoqing Xing1,2, Pengcheng Ma3, Qing Huang4
1Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy , China Pharmaceutical University , Nanjing 210009 , China.
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 Cmax 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.
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