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Prediction of the Pharmacokinetic Parameters of Triptolide in Rats Based on Endogenous Molecules in Pre-Dose Baseline Serum

2012; Public Library of Science; Volume: 7; Issue: 8 Linguagem: Inglês

10.1371/journal.pone.0043389

1932-6203

Linsheng Liu, Bei Cao, Jiye Aa, Zheng Tian, Jian Shi, Mengjie Li, Xinwen Wang, Chunyan Zhao, Wenjing Xiao, Xiaoyi Yu, Runbin Sun, Rongrong Gu, Jun Zhou, Liang Wu, Gang Hao, Xuanxuan Zhu, Guangji Wang,

Phytochemistry and biological activity of medicinal plants

Background Individual variances usually affect drug metabolism and disposition, and hence result in either ineffectiveness or toxicity of a drug. In addition to genetic polymorphism, the multiple confounding factors of lifestyles, such as dietary preferences, contribute partially to individual variances. However, the difficulty of quantifying individual diversity greatly challenges the realization of individualized drug therapy. This study aims at quantitative evaluating the association between individual variances and the pharmacokinetics. Methodology/Principal Findings Molecules in pre-dose baseline serum were profiled using gas chromatography mass spectrometry to represent the individual variances of the model rats provided with high fat diets (HFD), routine chows and calorie restricted (CR) chows. Triptolide and its metabolites were determined using high performance liquid chromatography mass spectrometry. Metabonomic and pharmacokinetic data revealed that rats treated with the varied diets had distinctly different metabolic patterns and showed differential Cmax values, AUC and drug metabolism after oral administration of triptolide. Rats with fatty chows had the lowest Cmax and AUC values and the highest percentage of triptolide metabolic transformation, while rats with CR chows had the highest Cmax and AUC values and the least percentage of triptolide transformation. Multivariate linear regression revealed that in baseline serum, the concentrations of creatinine and glutamic acid, which is the precursor of GSH, were linearly negatively correlated to Cmax and AUC values. The glutamic acid and creatinine in baseline serum were suggested as the potential markers to represent individual diversity and as predictors of the disposal and pharmacokinetics of triptolide. Conclusions/Significance These results highlight the robust potential of metabonomics in characterizing individual variances and identifying relevant markers that have the potential to facilitate individualized drug therapy.