Dose‐linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats

Abstract

The pharmacokinetics of oleanolic acid was evaluated in vitro and in vivo. From Caco-2 cell permeation studies, oleanolic acid was a low permeability compound with no directional effects, suggesting a low in vivo absorption mediated by a passive diffusion. Oleanolic acid was metabolically unstable following incubation with rat liver microsomes in the presence of NADPH. After intravenous injection at doses of 0.5, 1 and 2 mg/kg doses, oleanolic acid showed dose-linear pharmacokinetics as evidenced by unaltered CL (28.6-33.0 ml/min/kg), Vss (437-583 ml/kg), dose-normalized AUC (16.0-17.9 microg min/ml based on 1 mg/kg) and t1/2 (41.9-52.7 min). Following oral administration of oleanolic acid at doses of 10, 25 and 50 mg/kg, Tmax, t1/2, dose-normalized Cmax (66-74 ng/ml based on 25 mg/kg) and dose-normalized AUC (5.4-5.9 microg min/ml based on 25 mg/kg) were comparable between 25 and 50 mg/kg dose, but the plasma concentrations at 10 mg/kg dose were not measurable as they were below the limit of quantitation (2 ng/ml). The absolute oral bioavailability was 0.7% for oral doses of 25 and 50 mg/kg. The extent of urinary excretion was minimal for both i.v. and oral doses. The very low oral bioavailability of oleanolic acid could be due to a poor absorption and extensive metabolic clearance.

Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus

“…48 However, low oral bioavailability (0.7%) for oleanolic acid, an analogue of butulinic acid, was observed, implying poor absorption and extensive metabolite clearance. 49 These results indicate that butulinic acid can be used i.p. or dermal administration without a major problem.…”

A preliminary pharmacokinetic study of betulin, the main pentacyclic triterpene from extract of outer bark of birch (Betulae alba cortex)

“…S.c. administration even obtained a concentration of 0.33 µg/mL in dogs. It is known that OA is able to bind to plasmin and albumin [17,21], possibly explaining such high serum concentrations. Because of different absorption mechanisms by s.c. and i.p.…”

“…they have to be dissolved. Therefore, organic solvents, for example N,N-dimethyl-acetamide, are necessary [17], but they are not excipients of first choice for pharmaceutical usage [18]. In contrast, the solubility of BE in oil is approximately 3 mg/mL [2] which offers the possibility of topical application.…”

Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo

“…The conventional clinical formulations of OA are tablets and capsules, which possess significant first-pass effect of hepar and undergoes low dissolution in gastrointestinal tract because of the poor water solubility. [12][13][14] Therefore, it is essential to develop a novel dosage form for OA to improve the treatment efficiency for HCC.…”