Preclinical Pharmacokinetic and Pharmacodynamic Investigation of 5’-Methoxynobiletin from Ageratum conyzoides: In vivo and In silico Approaches

Authors: Faqueti LG, da Silva LAL, Moreira GSG, Kraus S, de Jesus GdSC, Honorato LA, de Araújo BV, dos Santos ARS, Biavatti MW
Publication: Pharmaceutical Research
Keywords: 5’-methoxynobiletin, antinociceptive activity, polymethoxyflavone, pre-clinical pharmacokinetics
Software: ADMET Predictor®
Therapeutic Areas: Inflammation

Abstract

Purpose
5’-methoxynobiletin (5’-MeONB), a polymethoxyflavone isolated from A. conyzoides, has shown anti-inflammatory property. Nevertheless, the antinociceptive activity and pre-clinical pharmacokinetics (PK) characteristics of 5’-MeONB remain unknown. Considering the anti-inflammatory potential of the 5’-MeONB, this study aimed to investigate the pre-clinical PK behavior of 5’-MeONB, as well as its time course antinociceptive activity.

Methods
5’-MeONB plasma concentrations were determined in Wistar rats after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) administration, and in Swiss mice after oral administration (100 mg/kg). Plasma samples were deproteinization and 5’-MeONB quantified by a validated UPLC-MS method. Additionally, the antinociceptive activity of 5’-MeONB was evaluated after 15, 30, 60, 180 and 360 min following oral administration on the acute nocifensive behavior of mice induced by formalin.

Results
5’-MeONB rats and mice plasma concentration–time profiles were best one-compartment model. After i.v. administration to rats, a short half-life, a high clearance and moderate volume of distribution at steady state were observed. Similar results were obtained after oral administration. The oral bioavailability ranged from 8 to 11%. Additionally, 5’-MeONB exhibited antinociceptive activity in both formalin phases, especially in the inflammatory phase of the model, inhibiting 68% and 91% of neurogenic and inflammatory responses, respectively, after 30 min of oral administration.

Conclusions
The results described here provide novel insights on 5’-MeONB pharmacokinetics and pharmacodynamic effect, serving as support for future studies to confirm this compound as anti-nociceptive and anti-inflammatory effective agent.

By Larissa Gabriela Faqueti, Layzon Antonio Lemos da Silva, Gabriela Salim Gomes Moreira, Scheila Kraus, Gustavo dos Santos Catarina de Jesus, Luciana Aparecida Honorato, Bibiana Verlindo de Araujo, Adair Roberto Soares dos Santos, Teresa Dalla Costa & Maique Weber Biavatti