Pharmacokinetic-Pharmacodynamic Analysis on Inflammation Rat Model after Oral Administration of Huang Lian Jie Du Decoction

Abstract

Huang-Lian-Jie-Du Decoction (HLJDD) is a classical Traditional Chinese Medicine (TCM) formula with heat-dissipating and detoxifying effects. It is used to treat inflammation-associated diseases. However, no systematic pharmacokinetic (PK) and pharmacodynamic (PD) data concerning the activity of HLJDD under inflammatory conditions is available to date. In the present study, the concentration-time profiles and the hepatic clearance rates (HCR) of 41 major components in rat plasma in response to the oral administration of a clinical dose of HLJDD were investigated by LC-QqQ-MS using a dynamic multiple reaction monitoring (DMRM) method. Additionally, the levels of 7 cytokines (CKs) in the plasma and the body temperature of rats were analyzed. Furthermore, a PK-PD model was established to describe the time course of the hemodynamic and anti-inflammatory effects of HLJDD. As one of the three major active constituents in HLJDD, iridoids were absorbed and eliminated more easily and quickly than alkaloids and flavonoids. Compared with the normal controls, the flavonoids, alkaloids and iridoids in inflamed rats exhibited consistently changing trends of PK behaviors, such as higher bioavailability, slower elimination, delays in reaching the maximum concentration (Tmax) and longer substantivity. The HCR of iridoids was different from that of alkaloids and flavonoids in inflamed rats. Furthermore, excellent pharmacodynamic effects of HLJDD were observed in inflamed rats. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, IL-10, and macrophage inflammatory protein-2 (MIP-2) and body temperature significantly decreased after the administration of HLJDD. Based on PK-PD modeling with the three-phase synchronous characterization of time-concentration-effect, flavonoids exhibited one mechanism of action in the anti-inflammatory process, while iridoids and alkaloids showed another mechanism of action. Taken together, the results demonstrated that HLJDD may restrain inflammation synergistically via its major constituents (alkaloids, flavonoids and iridoids). A correlation between the exposure concentration of different types of compounds and their anti-inflammatory effects in the body was shown. This study provides a comprehensive understanding of the anti-inflammatory activity of HLJDD.

Huanglian Jiedu decoction remodels the periphery microenvironment to inhibit Alzheimer’s disease progression based on the “brain-gut” axis through multiple integrated omics

“…It has been widely applied to treat cerebrovascular diseases, ischaemic stroke, and AD in many Asian countries for centuries [3][4][5][6]. In our previous studies, the chemical profile and haemodynamics of HLJDD were described in detail [7,8] . Sixty-nine compounds in HLJDD were identified, including mainly iridoids, alkaloids and flavonoids.…”

Huang-Lian Jie-Du decoction: a review on phytochemical, pharmacological and pharmacokinetic investigations

“…And the mean residence time were 0.9 ± 0.1, 1.8 ± 0.1, 4.3 ± 0.3, 5.7 ± 3.5, 4.4 ± 0.5, 4.7 ± 0.5, 4.3 ± 0.8, 3.0 ± 0.6 h, respectively. Compared with the normal control group, the PK behaviors of alkaloids, flavonoids, and iridoids in the inflammatory model exhibited a trend of continuous changes, including higher bioavailability, slower elimination, delays in reaching the C max and longer substantivity [169]. In addition, there were a handful of PK investigations of couplet medicines from HLJDD.…”

Pharmacokinetics of B-Ring Unsubstituted Flavones

“…The AUC last of baicalin and wogonin were 2.0- and 5.4-fold larger in a group of rats in which inflammation was induced with carrageenan (i.p. ), as compared with the control group (with no inflammation) [286].…”