Investigating the Contribution of Drug-Metabolizing Enzymes in Drug-Drug Interactions of Dapivirine and Miconazole.
Investigating the Contribution of Drug-Metabolizing Enzymes in Drug-Drug Interactions of Dapivirine and Miconazole.
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研究药物代谢酶在dapivirine和Miconazole的药物相互作用中的贡献。
DOI：
10.3390/pharmaceutics13122193
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发表时间：
2021-12-18
期刊：
影响因子：
5.4
通讯作者：
Rohan LC
中科院分区：
文献类型：
--
作者：
Valicherla GR;Graebing P;Zhang J;Zheng R;Nuttall J;Silvera P;Rohan LC
达匹韦林（DPV）是一种有效的NNRTI，用于预防艾滋病毒的性传播。在一项I期试验（IPM 028）中，发现同时使用DPV阴道环和抗真菌咪康唑（MIC）阴道胶囊会增加女性的DPV全身暴露量，表明可能存在药物相互作用。本研究的目的是使用雌性生殖道（FRT）局部表达的药物代谢酶（DME; CYP和UGT）研究DPV-MIC相互作用的机制。进行体外研究以评价DPV的代谢及其与DME的抑制和诱导潜力。此外，还研究了MIC对DPV代谢的影响以及DPV与DME的抑制潜力。我们的研究结果表明，DPV是CYP 1A 1和CYP 3A 4酶的底物，MIC通过抑制这两种酶显著降低DPV代谢。DPV对CYP 1A 1表现出强效抑制作用，对评价的6种β-内酰胺酶和8种UGT酶表现出中度/弱抑制作用。MIC显示对7种UGT酶的有效/中度抑制和对8种UGT酶的弱/无抑制。DPV和MIC的组合显示出对7种酶（1A 1、1A 2、1B 1、2B 6、2C 8、2C 19和3A 4）和4种UGT酶（1A 3、1A 6、1A 9和2B 7）的有效抑制。在原代人肝细胞中，DPV不是CYP 1A 2、CYP 2B 6和CYP 3A 4酶的诱导剂。因此，在IPM 028中观察到的DPV全身浓度增加可能是由于FRT中MIC对CYP 1A 1和CYP 3A 4酶的抑制导致DPV代谢降低。
Dapivirine (DPV) is a potent NNRTI used to prevent the sexual transmission of HIV. In a phase 1 trial (IPM 028), the concomitant use of a DPV vaginal ring and an antifungal miconazole (MIC) vaginal capsule was found to increase the systemic exposure to DPV in women, suggesting a potential for drug-drug interactions. This study’s objective was to investigate the mechanism of DPV-MIC interactions using drug-metabolizing enzymes (DMEs; CYPs and UGTs) that are locally expressed in the female reproductive tract (FRT). In vitro studies were performed to evaluate the metabolism of DPV and its inhibition and induction potential with DMEs. In addition, the impact of MIC on DPV metabolism and the inhibitory potential of DPV with DMEs were studied. Our findings suggest that DPV is a substrate of CYP1A1 and CYP3A4 enzymes and that MIC significantly decreased the DPV metabolism by inhibiting these two enzymes. DPV demonstrated potent inhibition of CYP1A1 and moderate/weak inhibition of the six CYP and eight UGT enzymes evaluated. MIC showed potent/moderate inhibition of seven CYP enzymes and weak/no inhibition of eight UGT enzymes. The combination of DPV and MIC showed potent inhibition of seven CYP enzymes (1A1, 1A2, 1B1, 2B6, 2C8, 2C19, and 3A4) and four UGT enzymes (1A3, 1A6, 1A9, and 2B7). DPV was not an inducer of CYP1A2, CYP2B6, and CYP3A4 enzymes in primary human hepatocytes. Therefore, the increased systemic concentrations of DPV observed in IPM 028 were likely due to the reduced metabolism of DPV because of CYP1A1 and CYP3A4 enzymes inhibition by MIC in the FRT.
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影响因子：
2
作者：
Niwa, T;Shiraga, T;Takagi, A
通讯作者：
Takagi, A
影响因子：
16.1
作者：
Nel, Annalene;van Niekerk, Neliette;Rosenberg, Zeda
通讯作者：
Rosenberg, Zeda
影响因子：
4.7
作者：
FARIN, FM;BIGLER, LG;OMIECINSKI, CJ
通讯作者：
OMIECINSKI, CJ
影响因子：
2
作者：
Niwa, T;Inoue-Yamamoto, S;Takagi, A
通讯作者：
Takagi, A
影响因子：
3.9
作者：
Bourcier, Karine;Hyland, Ruth;Jones, Barry
通讯作者：
Jones, Barry