*5.1. Atorvastatin*

Atorvastatin is a substrate of P-gp, OATPs, BCRP and CYP3As. Diabetes reduced expressions of intestinal P-gp, CYP3A and OATP1A5, while induced expressions of liver OATP1B2 and CYP3A. Intestinal BCRP was highly dependent upon diabetes course, which was decreased at an early phase of diabetes (10-day) but induced at a late phase (22-day). A pharmacokinetic study showed that oral plasma exposure was increased in 10-day diabetic rats, but decreased in 22-day diabetic rats. PBPK simulation demonstrated that contributions of these targeted protein to altered oral plasma exposure of atorvastatin were intestinal BCRP > hepatic OATP1B2 > hepatic CYP3A > intestinal CYP3A > intestinal P-gp > intestinal OATP1A5. The increased oral plasma atorvastatin exposure in 10-day diabetic rats and the decreased oral plasma atorvastatin exposure in 22-day diabetic rats were attributed to the altered intestinal BCRP [11].
