Both cMOAT/MRP2 and another unknown transporter(s) are responsible for the biliary excretion of glucuronide conjugate of the nonpeptide angiotensin II antagonist, telmisaltan.
Both cMOAT/MRP2 and another unknown transporter(s) are responsible for the biliary excretion of glucuronide conjugate of the nonpeptide angiotensin II antagonist, telmisaltan.
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发表时间：
2000-10
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通讯作者：
A. Nishino;Y. Kato;T. Igarashi;Y. Sugiyama
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作者：
A. Nishino;Y. Kato;T. Igarashi;Y. Sugiyama
已知小管多特异性有机阴离子转运蛋白（cMOAT/MRP 2）在阴离子外源性物质（包括多种类型的葡萄糖醛酸苷和谷胱甘肽结合物）跨胆小管膜转运中发挥重要作用。在本研究中，在Sprague-Dawley大鼠（SDR）和突变品系高胆红素血症大鼠（EHBR，其具有cMOAT/MRP 2遗传缺陷）中检查了替米沙坦（BIBR 277）及其葡糖苷酸的胆汁排泄。静脉推注BIBF 277后，仅观察到总放射性血浆浓度的时间曲线存在极轻微差异。在两种菌株中，约45%的给药剂量在240 min内排泄至胆汁中，胆汁中的大部分放射性为BIBR 277葡糖苷酸。在SDR和EHBR之间，未观察到BIBF 277及其葡萄糖醛酸苷的胆汁排泄存在显著差异，尽管EHBR中BIBF 277葡萄糖醛酸苷的血浆消失延迟。为了解释这些数据，在两种菌株中检查了肝微粒体对BIBR 277的葡萄糖醛酸化程度。EHBR中BIBF 277葡萄糖醛酸苷形成的V（max）值比SDR高2 - 3倍，而两种菌株的K（m）值相似。静脉推注BIBF 277葡萄糖醛酸苷后，EHBR中其血浆消失延迟，EHBR中的胆汁清除率约为SDR中的一半。这些结果表明，BIBR 277葡萄糖醛酸苷由cMOAT/MRP 2和另一种也在EHBR中表达的转运蛋白转运，并且BIBR 277葡萄糖醛酸化在EHBR中增强，导致两种菌株中葡萄糖醛酸苷的排泄相当。
Canalicular multispecific organic anion transporter (cMOAT/MRP2) is known to play a major role in the transport of anionic xenobiotics including many types of glucuronide and glutathione conjugates across the bile canalicular membrane. In the present study, the biliary excretion of telmisartan (BIBR 277) and its glucuronide was examined in Sprague-Dawley rats (SDRs) and also in mutant strain Eisai-hyperbilirubinemic rats (EHBR), which have a hereditary defect in cMOAT/MRP2. Only a minimal difference was observed in the time profile of the plasma concentration of total radioactivity after administration of an i.v. bolus of BIBR 277. About 45% of the administered dose was excreted into bile up to 240 min in both strains, most of the radioactivity in the bile being BIBR 277 glucuronide. No significant difference was observed in the biliary excretion of BIBR 277 and its glucuronide between SDRs and EHBR although the plasma disappearance of BIBR 277 glucuronide was delayed in EHBR. To explain these data, the extent of glucuronidation of BIBR 277 by liver microsomes was examined in both strains. The V(max) value for the formation of BIBR 277 glucuronide was 2 to 3 times higher in EHBR than in SDRs, whereas both strains had similar K(m) values. After an i.v. bolus administration of BIBR 277 glucuronide, its plasma disappearance was delayed in EHBR, the biliary clearance in EHBR being about half that in SDRs. These results suggest that BIBR 277 glucuronide is transported by both cMOAT/MRP2 and another transporter that is also expressed in EHBR, and that the BIBR 277 glucuronidation is enhanced in EHBR, resulting in comparable excretion of glucuronide in both strains.