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

Copaifera 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 non-volatile compounds of Copaifera duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using an 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 Copaifera duckei oleoresin, and blood was collected through their caudal vein for 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 (Ka) = 0.47 h-1, central and peripherial apparent volume of distribution (Vc/F and Vp/F) = 0.04 L and 2.48 L, apparent clearance (CL/F) = 0.15 L/h, and elimination half-life (t1/2) = 11.60 h; and of dihydro-ent-agathic acid were Ka = 0.28 h-1, Vc/F and Vp/F = 0.01 L and 0.18 L, CL/F = 0.04 L/h and t1/2 = 3.49 h. CL/F, Vc/F and Vp/F of ent- polyalthic acid are approximately 3.75, 4.00 and, 13.78 times fold the dihydro- ent-agathic ones.

Publikationsverlauf

Eingereicht: 22. November 2023

Angenommen nach Revision: 15. Mai 2024

Accepted Manuscript online:
15. Mai 2024