Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase--effect of cMOAT deficiency on hepatobiliary excretion in rats and of mdr1a/b gene disruption on tissue distribution in mice.
Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase--effect of cMOAT deficiency on hepatobiliary excretion in rats and of mdr1a/b gene disruption on tissue distribution in mice.
复制标题
DOI：
10.2133/dmpk.17.449
复制
发表时间：
2002-01-01
影响因子：
2.1
通讯作者：
Kojima, Junji
中科院分区：
文献类型：
--
作者：
Fujino, Hideki;Yamada, Iwao;Kojima, Junji
Pitavastatin 是 HMG-CoA 还原酶的有效竞争性抑制剂。在本研究中，为了阐明匹伐他汀的肝胆排泄，我们研究了 EHBR 中 (14)C-匹伐他汀的血浆浓度和胆汁排泄。我们还通过全身放射自显影和定量放射分析评估了匹伐他汀在 mdr1a/b 敲除小鼠中的分布。鉴于匹伐他汀在临床上的广泛应用以及药物相互作用的重要性，还研究了其对Pgp介导的ATP酶激活的抑制作用。服用(14)C-匹伐他汀后，SDR 和 EHBR 之间放射性的血浆浓度和胆汁排泄没有显着差异。在 mdr1a/b 敲除小鼠中检测到很少的放射性转移到大脑中，并且在匹伐他汀存在的情况下，人 Pgp 的 ATP 酶活性可以忽略不计。此外，在较宽浓度范围的匹伐他汀存在下，未发现维拉帕米对 Pgp 介导的 ATP 酶激活有抑制作用。这些结果表明cMOAT和Pgp介导的转运机制在匹伐他汀的分布中并未发挥主要作用。
Pitavastatin is a potent competitive inhibitor of HMG-CoA reductase. In the current study, to elucidate the hepatobiliary excretion of pitavastatin, we investigated the plasma concentration and biliary excretion of (14)C-pitavastatin in EHBR. We also evaluated the distribution of pitavastatin in mdr1a/b knockout mice by whole body autoradiography and quantitative radioassay. In view of the widespread clinical use of pitavastatin and the importance of drug-drug interaction, the inhibitory effect on Pgp-mediated activation of ATPase was also investigated. No marked difference was observed in the plasma concentration and biliary excretion of radioactivity between SDR and EHBR after dosing of (14)C-pitavastatin. Little radioactive transfer into the brain was detected in mdr1a/b knockout mice and the ATPase activity of human Pgp was negligible in the presence of pitavastatin. Moreover, no inhibitory effect on the Pgp-mediated activation of ATPase by verapamil was found in the presence of pitavastatin over a wide concentration range. These results indicated that a cMOAT and Pgp-mediated transport mechanism did not play a major role in the distribution of pitavastatin.