The prediction of the hepatic clearance of tanshinone IIA in rat liver subcellular fractions: accuracy improvement.
The in vivo hepatic clearance of tanshinone IIA in the rat was predicted using microsome, cytosol and S9 fractions combined with two different cofactor systems, NADPH-regenerating and UDPGA system. Two different models, the well stirred model and the parallel-tube model, were used in predicting the in vivo clearance in the rat. The in vivo clearance of tanshinone IIA was acquired from a pharmacokinetic study in rat. The results show that the prediction accuracy acquired from the microsome combined with the NADPH is poor. The in vivo clearance in the rat is almost 32 fold higher than the clearance predicted in microsome. The predicted clearance of the S9 model combined with both NADPH and UDPGA system is about 4 fold lower than the in vivo clearance. The predicted clearance of the cytosol combined with the two cofactor system is about 7 fold lower than the in vivo clearance. Although the prediction accuracy acquired from the S9 and cytosol system is not perfect, the prediction accuracy is improved in these two incubation systems. Using S9 combined with both the phase I and phase II metabolism can improve the prediction accuracy.
Li
Peng
P
Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210038, China.
Wang
Guang-Ji
GJ
Li
Jing
J
Zhang
Qian
Q
Liu
Xin
X
Khlentzos
Alexander
A
Roberts
Michael S
MS
D045784:Abietanes; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000378:metabolism* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism* / Q000648:ultrastructure; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010616:Phenanthrenes / Q000378:metabolism* / Q000493:pharmacokinetics; D011237:Predictive Value of Tests; D051381:Rats; D015203:Reproducibility of Results; D013347:Subcellular Fractions / Q000378:metabolism*; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D045784:Abietanes; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; C021751:tanshinone; D009243:NAD; D014535:Uridine Diphosphate Glucuronic Acid; D009249:NADP