The inhibition of hepatic Pxr-Oatp2 pathway mediating decreased hepatic uptake of rosuvastatin in rats with high-fat diet-induced obesity.

Purpose: Obesity affecting drug pharmacokinetics results in the risk of the therapeutic failure or toxic side effects of drugs increasing. Unfortunately, the pharmacokinetic data in obese patients still lack for majority of drugs. Therefore, our study principally investigated the effect of obesity induced by high fat-diet (HFD) on the pharmacokinetics of rosuvastatin and explored the underlying mechanism via the hepatic pregnane X receptor (Pxr)- organic anion transporting polypeptide 2 (Oatp2) signaling pathway and multidrug resistance-associated protein 2 (Mrp2) in rats.

Main Methods: Rats with obesity was induced by HFD for 4 weeks, and subsequently, the effect of obesity on the blood concentration, pharmacokinetic parameters and biliary excretion of rosuvastatin administrated intravenously and the hepatic uptake of rosuvastatin in the rat primary hepatocytes were evaluated. Additionally, in order to illuminate the underlying mechanism, the alterations of the mRNA expressions of Oatp2, Mrp2 and Pxr and the concentrations of lithocholic acid (LCA), glycine-LCA (GLCA) and taurine-LCA (TLCA) in liver were determined.

Key Findings: The blood concentration of rosuvastatin that has great relationship with the muscle toxicity increased in rats with HFD-induced obesity, which could be principally ascribed to the decreased hepatic uptake of rosuvastatin that was mainly resulted from the inhibition of hepatic Pxr-Oatp2 pathway.

Significance: The decreased hepatic uptake of rosuvastatin causing the increase of the rosuvastatin concentration in blood under the condition of HFD-induced obesity provides a cue for clinicians to reduce the rosuvastatin dose for obese patients to avoid the occurrence risk of the muscle toxicity of rosuvastatin.