Heterotropic Allosteric Modulation of CYP3A4 In Vitro by Progesterone: Evidence for Improvement in Prediction of Time Dependent Inhibition for Macrolides.

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Metabolism and Disposition Pub Date : 2024-10-29 DOI:10.1124/dmd.124.001820
Luc R A Rougee, Pooja V Hegde, Kaitlin Shin, Trent L Abraham, Alec Bell, Stephen D Hall
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Abstract

Predictions of drug-drug interactions resulting from time-dependent inhibition (TDI) of CYP3A4 have consistently overestimated or mis-predicted (i.e. false positives) the interaction that is observed in vivo. Recent findings demonstrated that the presence of the allosteric modulator progesterone (PGS) in the in vitro assay could alter the in vitro kinetics of CYP3A4 TDI with inhibitors that interact with the heme moiety, such as metabolic-intermediate complex (MIC) forming inhibitors. The impact of the presence of 100 µM PGS on the TDI of molecules in the class of macrolides typically associated with MIC formation was investigated. Presence of PGS resulted in varied responses across the inhibitors tested. The TDI signal was eliminated for five inhibitors, and unaltered in the case of one, fidaxomicin. The remaining molecules erythromycin, clarithromycin, and troleandomycin, were observed to have a decrease in both potency and maximum inactivation rate ranging from 1.7-fold to 6.7-fold. These changes in TDI kinetics led to a >90% decrease in inactivation efficiency. In order to determine in vitro conditions that could reproduce in vivo inhibition, varied concentrations of PGS were incubated with clarithromycin and erythromycin. Resulting in vitro TDI kinetics were incorporated into dynamic physiologically-based pharmacokinetic (PBPK) models to predict clinically observed interactions. The results suggested that a concentration of ~45 µM PGS would result in TDI kinetic values that could reproduce in vivo observations and could potentially improve predictions for CYP3A4 TDI. Significance Statement The impact of the allosteric heterotropic modulator progesterone on the CYP3A4 time-dependent inhibition kinetics was quantified for a set of metabolic-intermediate complex forming mechanism-based inhibitors. We identify the in vitro conditions that optimally predict time-dependent inhibition for in vivo drug-drug interactions through dynamic physiologically-based pharmacokinetic modeling. The optimized assay conditions improve in vitro to in vivo translation and prediction of time-dependent inhibition.

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黄体酮对体外 CYP3A4 的异向异构调节:改进大环内酯类药物时间依赖性抑制预测的证据。
对 CYP3A4 的时间依赖性抑制(TDI)所导致的药物间相互作用的预测一直高估或误测(即假阳性)体内观察到的相互作用。最近的研究结果表明,体外检测中异位调节剂黄体酮(PGS)的存在会改变 CYP3A4 TDI 与血红素分子相互作用的抑制剂(如代谢中间复合物(MIC)形成抑制剂)的体外动力学。我们研究了 100 µM PGS 的存在对通常与 MIC 形成有关的大环内酯类分子 TDI 的影响。PGS 的存在导致所测试的抑制剂产生了不同的反应。五种抑制剂的 TDI 信号被消除,一种抑制剂(非达霉素)的 TDI 信号未发生变化。其余的红霉素、克拉霉素和曲莱霉素分子的效力和最大失活率都下降了 1.7 倍到 6.7 倍不等。TDI 动力学的这些变化导致灭活效率下降了 90% 以上。为了确定能再现体内抑制作用的体外条件,将不同浓度的 PGS 与克拉霉素和红霉素进行了孵育。体外 TDI 动力学结果被纳入动态生理药代动力学(PBPK)模型,以预测临床观察到的相互作用。结果表明,约 45 µM 的 PGS 浓度将产生可再现体内观察结果的 TDI 动力学值,并有可能改善对 CYP3A4 TDI 的预测。意义声明 针对一组基于代谢-中间复合物形成机制的抑制剂,量化了异构异向调节剂孕酮对 CYP3A4 时间依赖性抑制动力学的影响。通过基于生理学的动态药代动力学建模,我们确定了可最佳预测体内药物间相互作用的时间依赖性抑制的体外条件。优化的检测条件提高了从体外到体内的转化和时间依赖性抑制作用的预测。
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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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