Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
J Pharm Sci. 2017 Sep;106(9):2671-2677. doi: 10.1016/j.xphs.2017.04.027. Epub 2017 Apr 27.
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) 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) and the oral bioavailability (F) 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 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 but also the increase in F caused the significant increase in the AUC 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.
本研究旨在探讨大鼠体内口服阿托伐他汀（ATV）和利福平（RIF）的药物-药物相互作用（DDI）。采用同位素 IV 法分析 ATV 的全身暴露增加（AUC），即口服 ATV 后静脉注射少量氘标记的 ATV（ATV-d5）。假设 ATV-d5 与 ATV 具有相同的药代动力学特性，这种方法可以在单次实验中计算每个大鼠的 ATV 系统清除率（CL）和口服生物利用度（F）。RIF 被口服预处理给大鼠以抑制有机阴离子转运多肽 1B1（OATP1B1）。通过对每个大鼠的药代动力学参数进行分析，结果表明 ATV 的 AUC 随着 RIF 的血浆水平而增加，表明 RIF 吸收的个体差异导致 DDI 的程度存在较大的变异性。此外，结果表明，不仅 CL 的降低，而且 F 的增加也导致 ATV 的 AUC 显著增加。总之，与影响口服药物吸收和消除过程的传统方法相比，同位素 IV 法在分析 DDI 方面具有多种优势。
