Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro.
Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro.
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人 UDP-葡萄糖醛酸基转移酶 2B4 和 2B7 负责体外萘哌地尔葡萄糖醛酸化
DOI：
10.3389/fphar.2017.00984
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发表时间：
2017
影响因子：
5.6
通讯作者：
Luo CF
中科院分区：
文献类型：
--
作者：
Liu XW;Rong Y;Zhang XF;Huang JJ;Cai Y;Huang BY;Zhu L;Wu B;Hou N;Luo CF
萘哌地尔（NAF）被广泛用于治疗良性前列腺增生和预防老年男性前列腺癌。这些患者接受药物组合，这涉及药物相互作用的高风险。NAF表现出上级功效，但必须以比其它治疗药物高得多的剂量施用。我们以前表明，NAF对映体的广泛葡萄糖醛酸化导致生物利用度差。然而，NAF对映体的代谢途径和作用机制仍有待阐明。本研究旨在鉴定负责NAF对映体葡萄糖醛酸化的人UDP-葡萄糖醛酸转移酶（UGT），并研究NAF对UGT活性的潜在抑制作用。主要代谢部位为肝脏和肾脏，并与肠道进行了比较。对12种重组UGT的筛选表明，UGT 2B 7主要促进两种对映体的代谢。此外，R（+）-NAF、UGT 2B 7的酶动力学（平均Km，21 μM;平均Vmax，1043 pmol/min/mg）显示活性显著高于UGT 2B 4和UGT 1A 9。UGT 2B 4（平均Km，55 μM;平均Vmax，1976 pmol/min/mg）和UGT 2B 7（平均Km，38 μM;平均Vmax，1331 pmol/min/mg）对S（-）-NAF葡萄糖醛酸化的催化作用显著高于UGT 1A 9。在人肝微粒体中，R（+）-NAF和S（-）-NAF也抑制UGT 1A 9：R（+）-NAF和S（-）-NAF的平均Ki值分别为10.0 μM和11.5 μM。这些数据表明，UGT 2B 7是介导R（+）-NAF和S（-）-NAF葡萄糖醛酸化的主要酶。UGT 2B 4在NAF对映体的立体选择性代谢中起关键作用。R（+）-NAF和S（-）-NAF可抑制UGT 1A 9。了解NAF对映体的代谢，特别是它们与代谢酶的相互作用，将有助于阐明潜在的药物相互作用，并优化这种药物的管理。
Naftopidil (NAF) is widely used for the treatment of benign prostatic hyperplasia and prevention of prostate cancer in elderly men. These patients receive a combination of drugs, which involves high risk for drug–drug interaction. NAF exhibits superior efficacy but must be administered at a much higher dosage than other therapeutic drugs. We previously showed that extensive glucuronidation of NAF enantiomers caused poor bioavailability. However, the metabolic pathway and mechanism of action of NAF enantiomer remain to be elucidated. The present study was performed to identify the human UDP-glucuronosyltransferases (UGTs) responsible for the glucuronidation of NAF enantiomers and to investigate the potential inhibition of UGT activity by NAF. The major metabolic sites examined were liver and kidney, which were compared with intestine. Screening of 12 recombinant UGTs showed that UGT2B7 primarily contributed to the metabolism of both enantiomers. Moreover, enzyme kinetics for R(+)-NAF, UGT2B7 (mean Km, 21 μM; mean Vmax, 1043 pmol/min/mg) showed significantly higher activity than observed for UGT2B4 and UGT1A9. UGT2B4 (mean Km, 55 μM; mean Vmax, 1976 pmol/min/mg) and UGT2B7 (mean Km, 38 μM; mean Vmax, 1331 pmol/min/mg) showed significantly higher catalysis of glucuronidation of S(-)-NAF than UGT1A9. In human liver microsomes, R(+)-NAF and S(-)-NAF also inhibited UGT1A9: mean Ki values for R(+)-NAF and S(-)-NAF were 10.0 μM and 11.5 μM, respectively. These data indicate that UGT2B7 was the principal enzyme mediating glucuronidation of R(+)-NAF and S(-)-NAF. UGT2B4 plays the key role in the stereoselective metabolism of NAF enantiomers. R(+)-NAF and S(-)-NAF may inhibit UGT1A9. Understanding the metabolism of NAF enantiomers, especially their interactions with metabolic enzymes, will help to elucidate potential drug–drug interactions and to optimize the administration of this medicine.
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影响因子：
3.9
作者：
Ohno, Shuji;Nakajin, Shizuo
通讯作者：
Nakajin, Shizuo
影响因子：
3.4
作者：
Knights, Kathleen M.;Rowland, Andrew;Miners, John O.
通讯作者：
Miners, John O.
影响因子：
6.7
作者：
Kuypers, DRJ;Naesens, M;Vanrenterghem, Y
通讯作者：
Vanrenterghem, Y
影响因子：
6.4
作者：
Kanda, Hideki;Ishii, Kenichiro;Sugimura, Yoshiki
通讯作者：
Sugimura, Yoshiki
影响因子：
3.9
作者：
Sato, Yuichiro;Nagata, Masanori;Usui, Takashi
通讯作者：
Usui, Takashi