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Prediction of atorvastatin pharmacokinetics in high-fat diet and low-dose streptozotocin induced diabetic rats using a semi-physiologically based pharmacokinetic model involving both enzymes and transporters.

著者 Wang Z , Yang H , Xu J , Zhao K , Chen Y , Liang L , Li P , Chen N , Geng D , Zhang X , Liu X , Liu L
Drug Metab Dispos.2019 Aug 09 ; ():.
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Atorvastatin is a substrate of cytochrome P450 3a (Cyp3a), organic anion transporting polypeptides (Oatps), breast cancer resistance protein (Bcrp) and P-glycoprotein (P-gp). We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model involving both enzyme and transporters for predicting contributions of altered function and expression of Cyp3a and transporters to atorvastatin transport in diabetic rats by combination of high-fat diet feeding and low-dose streptozotocin injection. Atorvastatin metabolism and transport parameters came from in situ intestinal perfusion, primary hepatocytes and intestinal/hepatic microsomes. Expressions and functions of these proteins and their contributions were estimated. The results showed that diabetes increased expression of hepatic Cyp3a, Oatp1b2 and P-gp, but decreased expression of intestinal Cyp3a, Oatp1a5 and P-gp. Expression and function of intestinal Bcrp were significantly decreased in 10-day diabetic rats but increased in 22-day diabetic rats. The developed semi-PBPK model was successfully used to predict atorvastatin pharmacokinetics following oral and intravenous dose to rats based on alterations in Cyp3a and transporters by diabetes. Contributions to oral atorvastatin pharmacokinetics were intestinal Oatp1a5<intestinal P-gp<intestinal Cyp3a<hepatic Cyp3a <hepatic Oatp1b2<intestinal Bcrp. Contributions of decreased expression and function of intestinal Cyp3a and P-gp by diabetes to oral atorvastatin plasma exposure were almost attenuated by increased expression and function of hepatic Cyp3a and Oatp1b2. Opposite alterations in oral plasma atorvastatin exposure between 10-day and 22-day diabetic rats may be explained by altered intestinal Bcrp. In conclusion, altered atorvastatin pharmacokinetics by diabetes was synergistic effects of altered intestinal/hepatic Cyp3a and transporters and could be predicted using the developed semi-PBPK. SIGNIFICANCE STATEMENT: The current work in our laboratory can be applied to changes in the proportion of protein content to construct physiological pharmacokinetic models. Changes in the expression level of a particular protein can be used to predict changes in the pharmacokinetic behavior of the drug under disease conditions. The developed semi-PBPK is often linked to alterations in function and expression of enzymes and transporters by disease. Theoretically, the model may be applied to predict pharmacokinetic behavior of the other drugs by other diseases if alterations in expression and function of enzymes and transporters were available.
PMID: 31399507 [PubMed - as supplied by publisher]
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