Jing Wanghui, Liu Ruilin, Du Wei, Luo Zhimin, Guo Pengqi, Zhang Ting, Zeng Aiguo, Chang Chun, Fu Qiang
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China.
Molecules. 2016 Mar 8;21(3):314. doi: 10.3390/molecules21030314.
A vast number of structural modifications have been performed for khellactone derivatives (KDs) that have been widely concerned owing to their diverse biological properties, including anti-hypertension, anti-HIV, reversing P-glycoprotein (P-gp) mediated multidrug resistance, and anti-inflammation effects, to find the most active entity. However, extensive metabolism of KDs results in poor oral bioavailability, thus hindering the clinical trial performance of those components. The primary metabolic pathways have been revealed as hydrolysis, oxidation, acyl migration, and glucuronidation, while carboxylesterases and cytochrome P450 3A (CPY3A), as well as UDP-glucuronosyltransferases (UGTs) primarily mediate these metabolic pathways. Attention was mainly paid to the pharmacological features, therapeutic mechanisms and structure-activity relationships of KDs in previous reviews, whereas their pharmacokinetic and metabolic characteristics have seldom been discussed. In the present review, KDs' metabolism and their pharmacokinetic properties are summarized. In addition, the structure-metabolism relationships of KDs and the potential drug-drug interactions (DDIs) induced by KDs were also extensively discussed. The polarity, the acyl groups substituted at C-3' and C-4' positions, the configuration of C-3' and C-4', and the moieties substituted at C-3 and C-4 positions play the determinant roles for the metabolic profiles of KDs. Contributions from CYP3A4, UGT1A1, P-gp, and multidrug resistance-associated protein 2 have been disclosed to be primary for the potential DDIs. The review is expected to provide meaningful information and helpful guidelines for the further development of KDs.
由于其多样的生物学特性，包括抗高血压、抗HIV、逆转P-糖蛋白（P-gp）介导的多药耐药性以及抗炎作用，凯林内酯衍生物（KDs）受到了广泛关注，人们对其进行了大量的结构修饰以寻找最具活性的实体。然而，KDs的广泛代谢导致口服生物利用度较差，从而阻碍了这些成分的临床试验表现。已揭示其主要代谢途径为水解、氧化、酰基迁移和葡萄糖醛酸化，而羧酸酯酶和细胞色素P450 3A（CPY3A）以及尿苷二磷酸葡萄糖醛酸转移酶（UGTs）主要介导这些代谢途径。以往的综述主要关注KDs的药理特性、治疗机制和构效关系，而很少讨论其药代动力学和代谢特征。在本综述中，总结了KDs的代谢及其药代动力学性质。此外，还广泛讨论了KDs的结构-代谢关系以及KDs诱导的潜在药物-药物相互作用（DDIs）。C-3'和C-4'位取代的酰基、C-3'和C-4'的构型以及C-3和C-4位取代的部分对KDs的代谢谱起决定性作用。已揭示CYP3A4、UGT1A1、P-gp和多药耐药相关蛋白2对潜在的DDIs起主要作用。本综述有望为KDs的进一步开发提供有意义的信息和有用的指导。
