Prediction of the pharmacokinetic parameters of triptolide in rats based on endogenous molecules in pre-dose baseline serum.
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.


RESULTS
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 C(max) values, AUC and drug metabolism after oral administration of triptolide. Rats with fatty chows had the lowest C(max) and AUC values and the highest percentage of triptolide metabolic transformation, while rats with CR chows had the highest C(max) 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 C(max) 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
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.
Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Linsheng
L
Liu
Bei
B
Cao
Jiye
J
Aa
Tian
T
Zheng
Jian
J
Shi
Mengjie
M
Li
Xinwen
X
Wang
Chunyan
C
Zhao
Wenjing
W
Xiao
Xiaoyi
X
Yu
Runbin
R
Sun
Rongrong
R
Gu
Jun
J
Zhou
Liang
L
Wu
Gang
G
Hao
Xuanxuan
X
Zhu
Guangji
G
Wang
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D031204:Caloric Restriction; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000097:blood*; D059305:Diet, High-Fat; D004224:Diterpenes / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D004852:Epoxy Compounds / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D008401:Gas Chromatography-Mass Spectrometry; D018698:Glutamic Acid / Q000097:blood*; D016014:Linear Models; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D015999:Multivariate Analysis; D010616:Phenanthrenes / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide; D018698:Glutamic Acid; D003404:Creatinine