Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
HIV Med. 2021 Nov;22(10):898-906. doi: 10.1111/hiv.13136. Epub 2021 Jul 30.
The World Health Organization recommends that all countries adopt dolutegravir-based antiretroviral therapy as the preferred regimen for all individuals living with HIV. Levonorgestrel is a commonly used hormonal contraceptive, which undergoes drug-drug interactions with some antiretrovirals, but the potential interaction between dolutegravir and levonorgestrel has not been examined. We aimed to evaluate cytochrome P450 (CYP)-mediated levonorgestrel metabolism and quantify the effects of dolutegravir on levonorgestrel apparent intrinsic clearance (CL ) and CYP gene expression.
In vitro CYP-mediated CL of levonorgestrel was quantified using a recombinant human CYP (rhCYP) enzyme system. A primary human hepatocyte model of drug metabolism was used to assess the effects of dolutegravir on (1) levonorgestrel CL , using liquid chromatography-tandem mass spectrometry, and (2) the expression of specific CYP enzymes, using quantitative real-time polymerase chain reaction.
Levonorgestrel clearance was mediated by multiple rhCYPs, including rhCYP3A4. Under control conditions, levonorgestrel CL was 22.4 ± 5.0 μL/min/10 hepatocytes. Incubation with 43.1 nM of unbound dolutegravir elevated levonorgestrel CL to 31.4 ± 7.8 µL/min/10 hepatocytes (P = 0.168), while 142.23 nM increased levonorgestrel CL to 37.0 ± 2.9 µL/min/10 hepatocytes (P = 0.012). Unbound dolutegravir ≥ 431 nM induced expression of CYP3A4 (≥ two-fold) in a dose-dependent manner, while 1.44 μM of unbound dolutegravir induced CYP2B6 expression 2.2 ± 0.3-fold (P = 0.0004).
In summary, this in vitro study suggests that dolutegravir has the potential to increase hepatic clearance of levonorgestrel by inducing both CYP3A and non-CYP3A enzymes. The observed in vitro dolutegravir-levonorgestrel drug-drug interaction should be further examined in clinical studies.
世界卫生组织建议所有国家将基于多替拉韦的抗逆转录病毒疗法作为所有艾滋病毒感染者的首选方案。左炔诺孕酮是一种常用的激素避孕药，它与一些抗逆转录病毒药物发生药物-药物相互作用，但多替拉韦和左炔诺孕酮之间的潜在相互作用尚未被研究。我们旨在评估细胞色素 P450（CYP）介导的左炔诺孕酮代谢，并量化多替拉韦对左炔诺孕酮表观内在清除率（CL）和 CYP 基因表达的影响。
使用重组人 CYP（rhCYP）酶系统定量测定体外 CYP 介导的左炔诺孕酮 CL。使用药物代谢的人原代肝细胞模型，通过液相色谱-串联质谱法评估多替拉韦对（1）左炔诺孕酮 CL 的影响，以及通过实时定量聚合酶链反应评估（2）特定 CYP 酶表达的影响。
左炔诺孕酮清除由多种 rhCYPs 介导，包括 rhCYP3A4。在对照条件下，左炔诺孕酮 CL 为 22.4±5.0μL/min/10 个肝细胞。孵育 43.1nM 未结合的多替拉韦将左炔诺孕酮 CL 提高至 31.4±7.8μL/min/10 个肝细胞（P=0.168），而 142.23nM 将左炔诺孕酮 CL 提高至 37.0±2.9μL/min/10 个肝细胞（P=0.012）。未结合的多替拉韦≥431nM 以剂量依赖性方式诱导 CYP3A4 表达（≥两倍），而 1.44μM 未结合的多替拉韦诱导 CYP2B6 表达 2.2±0.3 倍（P=0.0004）。
总之，这项体外研究表明，多替拉韦通过诱导 CYP3A 和非 CYP3A 酶，有可能增加左炔诺孕酮的肝清除率。在临床研究中应进一步研究观察到的多替拉韦-左炔诺孕酮药物相互作用。
