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

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), V ss (437–583 ml/kg), dose‐normalized AUC (16.0–17.9 µg min/ml based on 1 mg/kg) and t 1/2 (41.9–52.7 min). Following oral administration of oleanolic acid at doses of 10, 25 and 50 mg/kg, T max , t 1/2 , dose‐normalized C max (66–74 ng/ml based on 25 mg/kg) and dose‐normalized AUC (5.4–5.9 µg 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. Copyright © 2007 John Wiley & Sons, Ltd.