Population Pharmacokinetic of the Diterpenes ent-Polyalthic Acid and Dihydro-ent-Agathic Acid from Copaifera Duckei Oil Resin in Rats

Abstract

AbstractCopaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h−1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h−1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.