title: Pharmacokinetic and Metabolic Characteristics of Herb-Derived Khellactone Derivatives, A Class of Anti-HIV and Anti-Hypertensive: A Review.
abstract: 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.
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China. jingwanghui1987@163.com.
authors.forename: Wanghui
authors.initials: W
authors.lastname: Jing
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China. lrlxjtu1987@xjtu.edu.cn.
authors.forename: Ruilin
authors.initials: R
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China. duwei82@xjtu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China. luozm0930@163.com.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Luo
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China. guopengqi@stu.xjtu.edu.cn.
authors.forename: Pengqi
authors.initials: P
authors.lastname: Guo
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China. zhangting1234@stu.xjtu.edu.cn.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China. agzeng@xjtu.edu.cn.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Zeng
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China. changchun@xjtu.edu.cn.
authors.forename: Chun
authors.initials: C
authors.lastname: Chang
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Street, Xi'an 710061, Shannxi, China. fuqiang@xjtu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D003374:Coumarins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D010084:Oxidation-Reduction; D010936:Plant Extracts / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D000959:Antihypertensive Agents; D003374:Coumarins; D010936:Plant Extracts; C520900:khellactone
keywords: drug development; drug-drug interactions; khellactone derivatives; metabolism; pharmacokinetics; structure-metabolism relationship