Quantitative Analysis of the Transporter Mediated drug-drug Interaction Between Atorvastatin and Rifampicin using a Stable Isotope-IV Method
2017
Abstract This study aims to investigate the drug-drug interactions (DDIs) between orally administered atorvastatin (ATV) and rifampicin (RIF) in rats. The isotope-IV method was used for the analysis of the increased systemic exposure (AUC po ) of ATV, in which a small amount of deuterium-labeled ATV (ATV-d5) was intravenously injected after oral administration of ATV. By assuming ATV-d5 showed same pharmacokinetic properties with ATV, this method enabled to calculate the systemic clearance (CL tot ) and the oral bioavailability ( F oral ) of ATV for each individual rat in a single experiment. RIF was orally pretreated to rats to inhibit the organic anion transporting polypeptide 1B1 (OATP1B1). From the analysis using pharmacokinetic parameters in each rat, it was revealed that the AUC po of ATV increased depending on the plasma level of RIF, showing that the interindividual difference in the absorption of RIF caused the large variability in the extent of DDI. Furthermore, it was indicated that not only the decrease in CL tot but also the increase in F oral caused the significant increase in the AUC po of ATV. In conclusion, the isotope-IV method possesses various advantages over the conventional method for the analysis of DDIs which affects both absorption and elimination processes of oral drugs.
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