College of Pharmacy, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Innovative Drug Development and Evaluation, School of Pharmaceutical Sciences, Hebei Medical University, Shijiazhuang, China.
Department of Digestive Endoscopy, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang, China.
Environ Toxicol Pharmacol. 2020 Nov;80:103487. doi: 10.1016/j.etap.2020.103487. Epub 2020 Sep 1.
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.
在新药中，超过 90%的活性药物成分（APIs）或已上市药物的溶解度和生物利用度较差，这限制了药物制剂的发展。利用涉及 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。在 CMC 形式中注册的大多数新药都来自已上市药物，并且这些药物与细胞色素 P-450（CYP）酶之间的相互作用已有充分记录。然而，尚不清楚是否应重新评估已上市药物的 CMC 与 CYP 酶之间的相互作用。为了澄清这个问题，选择了三种基于二氟尼柳（Dip）的 CMC，包括 Dip-苯甲酸（BA）共晶、Dip-2-羟基苯甲酸（2HB）盐和 Dip-4-羟基苯甲酸（4HB）盐共晶，以研究与 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 测量基于 Dip 的 CMC 及其鸡尾酒探针药物的代谢物。基于 Dip 的 CMC 不仅改变了 Dip 对 CYP 酶的抑制或激活作用，而且改变了 rCYPs 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 的抑制作用增加；与 Dip-2HB 和 Dip-4HB 相比，Dip-BA、Dip-2HB 和 Dip-4HB 对 CYP3A4 的抑制作用增加；与 Dip-2HB 和 Dip-4HB 相比，Dip-BA 对 CYP2E1 的抑制作用增加。与 Dip-2HB 和 Dip-4HB 相比，Dip 和 Dip-HCl 对 CYP2C19 的抑制作用降低，与 Dip-4HB 对 CYP2E1 的抑制作用降低。改变 Dip CMC 对 Dip 与 CYP 酶相互作用的影响并非归因于 Dip 和各自前体的简单叠加，而可能是由于 Dip 和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 与 CYP 酶之间的相互作用。此外，这些结果进一步表明，当使用 CMC 策略设计新药时，甚至对于具有已知代谢特征的已上市药物的 CMC，都应重新评估与 CYP 酶的相互作用。
