Fujino Hideki, Saito Tsuyoshi, Ogawa Shin-Ichiro, Kojima Junji
Tokyo New Drug Research Laboratories I, Kowa Company Ltd, 2-17-43 Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
J Pharm Pharmacol. 2005 Oct;57(10):1305-11. doi: 10.1211/jpp.57.10.0009.
The purpose of this study was to gain a better understanding of the transport mechanism of pitavastatin, a novel synthetic HMG-CoA reductase inhibitor. Experiments were performed using oocytes of Xenopus laevis expressing several solute carrier (SLC) transporters and recombinant membrane vesicles expressing several human ABC transporters. The acid form of pitavastatin was shown to be a substrate for human OATP1, OATP2, OATP8, OAT3 and NTCP, and for rat Oatp1 and Oatp4 with relatively low K(m) values. In contrast, these SLC transporters were not involved in the uptake of the lactone form. A significant stimulatory effect was exhibited by pitavastatin lactone, while the acid form did not exhibit ATPase hydrolysis of P-glycoprotein. In the case of breast cancer resistant protein (BCRP), the acid form of pitavastatin is a substrate, whereas the lactone form is not. Taking these results into consideration, several SLC and ABC transporters were identified as critical to the distribution and excretion of pitavastatin in the body. This study showed, for the first time, that acid and lactone forms of pitavastatin differ in substrate activity towards uptake and efflux transporters. These results will potentially contribute to the differences in the pharmacokinetic profiles of pitavastatin.
本研究的目的是更深入地了解新型合成HMG-CoA还原酶抑制剂匹伐他汀的转运机制。实验使用了表达多种溶质载体（SLC）转运蛋白的非洲爪蟾卵母细胞和表达多种人类ABC转运蛋白的重组膜囊泡来进行。匹伐他汀的酸形式被证明是人类OATP1、OATP2、OATP8、OAT3和NTCP以及大鼠Oatp1和Oatp4的底物，其K(m)值相对较低。相比之下，这些SLC转运蛋白不参与内酯形式的摄取。匹伐他汀内酯表现出显著的刺激作用，而酸形式则未表现出P-糖蛋白的ATP酶水解作用。就乳腺癌耐药蛋白（BCRP）而言，匹伐他汀的酸形式是底物，而内酯形式则不是。考虑到这些结果，确定了几种SLC和ABC转运蛋白对匹伐他汀在体内的分布和排泄至关重要。本研究首次表明，匹伐他汀的酸形式和内酯形式在对摄取和外排转运蛋白的底物活性方面存在差异。这些结果可能导致匹伐他汀药代动力学特征的差异。
