Strong inhibitory effect of medroxyprogesterone acetate (MPA) on UDP-glucuronosyltransferase (UGT) 2B7 might induce drug-drug interactions
Strong inhibitory effect of medroxyprogesterone acetate (MPA) on UDP-glucuronosyltransferase (UGT) 2B7 might induce drug-drug interactions
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DOI：
10.1691/ph.2010.0671
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发表时间：
2010-12-01
期刊：
影响因子：
1.6
通讯作者：
Yang, L.
中科院分区：
文献类型：
--
作者：
Huang, T.;Fang, Z. Z.;Yang, L.
本研究的目的是探讨醋酸甲羟孕酮（MPA）对四种重要的UGT亚型（UGT 1A 1，1A 6，1A 9和2B 7）的抑制作用。4-甲基伞形酮（4-MU）用作非选择性底物，重组UGT同种型用作酶源。结果表明，MPA对UGT 2B 7具有抑制作用（IC 50 = 29.3 +/- 1.5 μ M），对其他UGT亚型的影响可忽略不计。从Lineweaver-Burk和狄克逊图获得的结果表明，MPA竞争性抑制UGT 2B 7。计算的Ki值为7.2 μ M。基于MPA在人体肝脏中的浓度，预测了体内药物相互作用（DDI）的大小。计算的[1]/K-i值为0.31，这表明MPA与主要通过UGT 2B 7介导代谢的药物联合给药时可能发生DDI。
The aim of the present study was to investigate the inhibitory effects of medroxyprogesterone acetate (MPA) on four important UGT isoforms (UGT1A1, 1A6, 1A9 and 2B7). 4-methylumbelliferone (4-MU) was used as a nonselective substrate, and recombinant UGT isoforms were utilized as an enzyme source. The results showed that MPA exhibited inhibitory effects on UGT2B7 (IC50 = 29.3 +/- 1.5 mu M), with a negligible influence on other UGT isoforms. The results obtained from Lineweaver-Burk and Dixon plots showed that MPA competitively inhibited UGT2B7. The K-i value was calculated to be 7.2 mu M. Based on the concentration of MPA in human liver, the magnitude of in vivo drug-drug interaction (DDI) was predicted. The [1]/K-i value was calculated to be 0.31, which suggested that DDIs might occur when MPA was co-administered with drugs which mainly undergo UGT2B7-mediated metabolism.