Watanabe Hiroshi, Sugimoto Ryusei, Ikegami Komei, Enoki Yuki, Imafuku Tadashi, Fujimura Rui, Bi Jing, Nishida Kento, Sakaguchi Yoshiaki, Murata Michiya, Maeda Hitoshi, Hirata Kenshiro, Jingami Sachiko, Ishima Yu, Tanaka Motoko, Matsushita Kazutaka, Komaba Hirotaka, Fukagawa Masafumi, Otagiri Masaki, Maruyama Toru
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto, Japan.
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Biochem Pharmacol. 2017 Dec 1;145:192-201. doi: 10.1016/j.bcp.2017.08.016. Epub 2017 Aug 24.
Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. In SHPT rats, hepatic and intestinal CYP3A expression was suppressed, but the changes were recovered by the administration of the calcimimetic cinacalcet, a PTH suppressor. Under the same experimental conditions, a pharmacokinetic study using orally administered midazolam, a substrate for CYP3A, showed that the AUC was increased by 5 times in SHPT rats, but that was partially recovered by a cinacalcet treatment. This was directly tested in rat primary hepatocytes and intestinal Caco-2 cells where the expression of the CYP3A protein was down-regulated by PTH (1-34). In Caco-2 cells, PTH (1-34) down-regulated the expression of CYP3A mRNA, but an inactive PTH derivative (13-34) had no effect. 8-Bromo-cyclic adenosine monophosphate, a membrane-permeable cAMP analog, reduced mRNA expression of CYP3A whereas the inhibitors of PI3K, NF-κB, PKC and PKA reversed the PTH-induced CYP3A down-regulation. These results suggest that PTH down-regulates CYP3A through multiple signaling pathways, including the PI3K/PKC/PKA/NF-κB pathway after the elevation of intracellular cAMP, and the effect of PTH can be prevented by cinacalcet treatment.
慢性肾脏病（CKD）不仅会影响肾脏清除功能，还会影响非肾脏清除功能，同时伴有肾功能下降。尽管有研究表明，诸如在CKD条件下体内蓄积的尿毒症毒素等体液因子可能参与了与非肾脏药物清除相关的变化，但整个过程尚未完全明确。在本研究中，我们以继发性甲状旁腺功能亢进（SHPT）大鼠为模型，报道了中分子尿毒症毒素甲状旁腺激素（PTH）对药物代谢或转运蛋白表达的作用。在SHPT大鼠中，肝脏和肠道CYP3A的表达受到抑制，但通过给予拟钙剂西那卡塞（一种PTH抑制剂）可使这些变化得到恢复。在相同实验条件下，使用口服给予的CYP3A底物咪达唑仑进行的药代动力学研究表明，SHPT大鼠的AUC增加了5倍，但西那卡塞治疗可使其部分恢复。这在大鼠原代肝细胞和肠道Caco-2细胞中得到直接验证，其中PTH（1-34）可下调CYP3A蛋白的表达。在Caco-2细胞中，PTH（1-34）下调了CYP3A mRNA的表达，但无活性的PTH衍生物（13-34）则无此作用。膜通透性cAMP类似物8-溴环磷酸腺苷降低了CYP3A的mRNA表达，而PI3K、NF-κB、PKC和PKA的抑制剂可逆转PTH诱导的CYP3A下调。这些结果表明，PTH通过多种信号通路下调CYP3A，包括细胞内cAMP升高后的PI3K/PKC/PKA/NF-κB通路，且西那卡塞治疗可预防PTH的作用。
