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Interactions between dipfluzine-based complexes and cytochrome P450 enzymes: information on salt, cocrystal, and salt cocrystal complexes.
Environmental Toxicology and Pharmacology ( IF 4.3 ) Pub Date : 2020-09-01 , DOI: 10.1016/j.etap.2020.103487
Huan Wang 1 , Shiji Li 2 , Lili Liu 3 , Jing Wang 1 , Yongli Wang 4 , Wei Guo 1
Affiliation  

In the new drugs, greater than 90 % of active pharmaceutical ingredients (APIs) or marketed drugs have poor solubility and bioavailability, which restrict the development of pharmaceutical preparations. The use of crystalline molecular complexes (CMCs) involving API and biocompatible precursors to improve solubility has become a shortcut for new drug development. Most of the new drugs registered in CMC form are from postmarketing drugs, and the interaction between these drugs and cytochrome P-450 (CYP) enzymes is well documented. However, it is unclear whether the interactions between CMCs of postmarketing drugs and CYP enzymes should be re-evaluated. To clarify this problem, three dipfluzine (Dip)-based CMCs, including Dip-benzoic acid (BA) cocrystal, Dip-2-hydroxybenzoate (2HB) salt and Dip-4-hydroxybenzoate (4HB) salt-cocrystal, were chosen to investigate the interaction with CYP enzymes. Metabolites of Dip-based CMCs and cocktail probe drugs were measured via LC–MS/MS in the incubation reaction system comprising recombinant CYP enzymes (rCYPs) and human liver microsomes. Dip-based CMCs not only alter Dip-mediated inhibition or activation of CYP enzymes but also change the degree to which rCYPs are involved in Dip metabolism. Specifically, the inhibitory effects of Dip and Dip-HCl were increased compared with Dip-BA and Dip-2HB for CYP1A2; Dip-BA, Dip-2HB and Dip-4HB for CYP3A4; and Dip-BA for CYP2E1. The inhibitory effects of Dip and Dip-HCl were reduced compared with Dip-2HB and Dip-4HB for CYP2C19 and Dip-4HB for CYP2E1. The effects of the alterations of Dip CMCs on the interaction between Dip and CYP enzymes are not attributed to a simple superposition of Dip and the respective precursor and may be due to the presence of interaction forces between Dip and precursor molecules. These results are the first to provide preliminary experimental evidence that CMCs change the interaction between API and CYP enzymes. Moreover, these results further suggest the importance of re-evaluating interactions with CYP enzymes when CMC strategies are used to design new drugs and even for CMCs of postmarketing drugs with known metabolic characteristics.



中文翻译:

基于双氟嗪的复合物与细胞色素P450酶之间的相互作用:有关盐,共晶和盐共晶复合物的信息。

在新药中,超过90%的活性药物成分(API)或市售药物具有较差的溶解度和生物利用度,这限制了药物制剂的开发。使用涉及API和生物相容性前体的结晶分子复合物(CMC)来提高溶解度已成为新药开发的捷径。以CMC形式注册的大多数新药都来自上市后的药物,这些药物与细胞色素P-450(CYP)酶之间的相互作用已有充分的文献记载。但是,尚不清楚是否应重新评估上市后药物的CMC与CYP酶之间的相互作用。为了澄清这个问题,我们使用了三种基于Dipfluzine(Dip)的CMC,包括Dip-苯甲酸(BA)共晶体,Dip-2-羟基苯甲酸酯(2HB)盐和Dip-4-羟基苯甲酸酯(4HB)盐-共晶,被选择研究与CYP酶的相互作用。在包含重组CYP酶(rCYPs)和人肝微粒体的孵育反应系统中,通过LC-MS / MS测量了基于Dip的CMC和鸡尾酒探针药物的代谢物。基于Dip的CMC不仅可以改变Dip介导的CYP酶的抑制或激活,还可以改变rCYP参与Dip代谢的程度。具体而言,与Dip-BA和Dip-2HB相比,Dip和Dip-HCl对CYP1A2的抑制作用增强。CYP3A4的Dip-BA,Dip-2HB和Dip-4HB; 和CYP2E1的Dip-BA。与Dip-2HB和Dip-4HB对CYP2C19和Dip-4HB对CYP2E1相比,Dip和Dip-HCl的抑制作用有所降低。Dip CMC的改变对Dip和CYP酶之间相互作用的影响并非归因于Dip与相应前体的简单叠加,可能归因于Dip与前体分子之间存在相互作用力。这些结果首次提供了初步的实验证据,表明CMC改变了API和CYP酶之间的相互作用。此外,这些结果进一步表明,当使用CMC策略设计新药甚至是具有已知代谢特征的上市后药物的CMC时,重新评估与CYP酶的相互作用的重要性。这些结果首次提供了初步的实验证据,表明CMC改变了API和CYP酶之间的相互作用。此外,这些结果进一步表明,当使用CMC策略设计新药甚至是具有已知代谢特征的上市后药物的CMC时,重新评估与CYP酶的相互作用的重要性。这些结果首次提供了初步的实验证据,表明CMC改变了API和CYP酶之间的相互作用。而且,这些结果进一步表明,当使用CMC策略设计新药甚至是具有已知代谢特征的上市后药物的CMC时,重新评估与CYP酶的相互作用的重要性。

更新日期:2020-09-30
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