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Review
. 2016 Mar 8;21(3):314.
doi: 10.3390/molecules21030314.

Pharmacokinetic and Metabolic Characteristics of Herb-Derived Khellactone Derivatives, A Class of Anti-HIV and Anti-Hypertensive: A Review

Wanghui Jing  1 , Ruilin Liu  2 , Wei Du  3 , Zhimin Luo  4 , Pengqi Guo  5 , Ting Zhang  6 , Aiguo Zeng  7 , Chun Chang  8 , Qiang Fu  9
Affiliations
Review

Pharmacokinetic and Metabolic Characteristics of Herb-Derived Khellactone Derivatives, A Class of Anti-HIV and Anti-Hypertensive: A Review

Wanghui Jing et al. Molecules. .

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.

Keywords: drug development; drug-drug interactions; khellactone derivatives; metabolism; pharmacokinetics; structure-metabolism relationship.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The chemical structures of khellactone derivatives 1–23 which exhibit promising activity.
Figure 2
Figure 2
Proposed cracking rules of khellactone derivatives using electrospray ionization-tandem mass spectrometry.
Figure 3
Figure 3
Hydrolysis-initiated metabolic pathways of praeruptorin A (PA), which is a natural khellactone derivative in Peucedani Radix.
Figure 4
Figure 4
NADPH-independent hydrolysis and intra-molecular acyl migration of praeruptorin A (PA) in Caco-2 cells, in rat/human liver microsomes in the absence of NADPH-regenerating system, and in fresh rat plasma. LM: liver microsomes. The structures of the two cis-khellactone glucuronides were tentatively assigned on the basis of the speculation in [31].
Figure 5
Figure 5
Proposed oxidation pathways of praeruptorin A in vitro and in vivo.
Figure 6
Figure 6
Proposed oxidation-initiated metabolic pathways of 3′,4′-di-O-(S)-camphanoyl-3-cyanomethyl-4-methyl-(+)-cis-khellactone (CMDCK) in vitro.
Figure 7
Figure 7
Schematic illustration of the absorption, metabolism, distribution and excretion (ADME) courses of khellactone derivatives following oral administration. IM: intestinal microsomes; LM: liver microsomes; plasma CEs: carboxylesterases.
Figure 8
Figure 8
Schematic illustration of activation mechanisms of the potential drug-drug interactions (DDIs) initiated by KDs via CAR- and PXR-mediated pathways.
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