Evaluation of P450 Inhibition and Induction by Artemisinin Antimalarials in Human Liver Microsomes and Primary Human Hepatocytes
Evaluation of P450 Inhibition and Induction by Artemisinin Antimalarials in Human Liver Microsomes and Primary Human Hepatocytes
复制标题
青蒿素抗疟药对人肝微粒体和原代人肝细胞中 P450 抑制和诱导的评价
DOI：
10.1124/dmd.112.045765
复制
发表时间：
2012-09-01
影响因子：
3.9
通讯作者：
Goodlett, David R.
中科院分区：
文献类型：
--
作者：
Xing, Jie;Kirby, Brian J.;Goodlett, David R.
青蒿素类药物已成为耐多药地区的一线抗疟药物。然而，用青蒿素药物进行单一治疗会导致相对较高的复发率。细胞色素P450 （P450）介导的代谢的自动诱导，导致暴露减少，被认为是潜在的机制。为了更好地了解自身诱导和代谢药物-药物相互作用（ddi），我们利用人肝微粒体、重组P450酶和原代人肝细胞，评估了两种青蒿素药物——青好素（QHS）和双氢青蒿素（DHA）抑制或诱导的P450（特别是CYP2B6和CYP3A4）。结果表明，QHS是CYP2B6 （Ki 4.6 μM）的弱可逆抑制剂，而不是CYP3A4 (IC50 ~ 50 μM)，并且对CYP2B6或CYP3A4均没有可测量的时间依赖性抑制。DHA对CYP2B6和CYP3A4均无抑制作用（IC50 ~ 125 μM）。此外，QHS还能诱导CYP3A4 （Emax 3.5倍，EC50 5.9 μM）和CYP2B6 （Emax 1.9倍，EC50 0.6 μM）的活性。在研究的其他p450、UDP葡萄糖醛酸转移酶和转运蛋白中，QHS和DHA除了轻微诱导CYP1A2 （Emax 7.9倍，EC50 5.2 μM）和CYP2A6 （Emax 11.7倍，EC50 4.0 μM）的mRNA表达外，没有显著影响。p450介导的ddi的定量预测表明，由于CYP3A4活性增加1.9倍，CYP2B6活性增加1.6倍，AUCi/AUC比率下降至59%，QHS清除自动诱导。这些数据表明，QHS药物是P450酶的潜在诱导剂，可能与青蒿素药物相互作用（或缺乏相互作用）可能具有临床相关性。
Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism. To better understand the autoinduction and metabolic drug-drug interactions (DDIs), we evaluated the P450s (particularly CYP2B6 and CYP3A4) inhibited or induced by two artemisinin drugs, Qing-hao-su (QHS) and dihydroartemisinin (DHA) using human liver microsome, recombinant P450 enzymes, and primary human hepatocytes. The results suggested that QHS was a weak reversible inhibitor of CYP2B6 (Ki 4.6 μM), but not CYP3A4 (IC50 ∼ 50 μM) and did not show measurable time-dependent inhibition of either CYP2B6 or CYP3A4. DHA inhibited neither CYP2B6 nor CYP3A4 (IC50 > 125 μM). In addition, it was found that QHS induced the activity of CYP3A4 (Emax 3.5-fold and EC50 5.9 μM) and CYP2B6 (Emax 1.9-fold and EC50 0.6 μM). Of the other P450s, UDP glucuronosyltransferases, and transporters studied, QHS and DHA had no significant effect except for minor induction of mRNA expression of CYP1A2 (Emax 7.9-fold and EC50 5.2 μM) and CYP2A6 (Emax 11.7-fold and EC50 4.0 μM) by QHS. Quantitative prediction of P450-mediated DDIs indicate autoinduction of QHS clearance with the AUCi/AUC ratio decreasing to 59%, as a result of a 1.9-fold increase in CYP3A4 and a 1.6-fold increase in CYP2B6 activity. These data suggest that QHS drugs are potential inducers of P450 enzymes, and the possible drug interactions (or lack thereof) with artemisinin drugs may be clinically relevant.