Dual strategies to improve oral bioavailability of oleanolic acid: Enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes

• The OPCH composed of OPC and HA was prepared.
• OPCH was used to enhance solubility and permeability of OA.
• Ketoconazole (KCZ) was investigated to inhibit the metabolism of OA by CYP 3A.
• Pharmacokinetic parameters showed the maximum bioavailability of OPCH with KCZ.

Oleanolic acid (OA) is a typical BCS IV drug with low water-solubility and poor permeability, metabolized by cytochrome P450 (CYP) isozymes in the intestinal tract, such as CYP3A. These are the reasons for the low oral bioavailability of OA which have restricted its wide application. In this study, a solidified phospholipid complex (OPCH) composed of OA–phospholipid complex (OPC) and hydroxyapatite (HA) was prepared by simple solvent evaporation. OPC was used to improve the liposolubility of OA, and HA was used to improve the flowability of OPC. Ketoconazole (KCZ, inhibitor of CYP3A) was co-administrated with OPCH to inhibit the metabolism of OA by CYP3A in the intestine. DSC, PXRD, SEM and IR analysis confirmed the formation of OPC and OPCH. Compared with the water-solubility and n-octanol solubility of OA, that of OPCH was increased nearly 15.3-fold and 3.19-fold, respectively. An in vitro dissolution study showed that the cumulative dissolution rate of OPCH was nearly 2.23-fold and 4.57-fold higher than that of OA and OPC at 2 h. Single-pass intestinal perfusion studies showed that the absorption of OA from OPCH was increased nearly 1.6–2.6-fold compared with that of pure OA and this was mainly due to the improved permeability and was further increased by OPCH with KCZ 1.2–2.4-fold compared with that of OPCH because KCZ inhibited metabolism of OA by CYP3A. A pharmacokinetic study of OPCH in rats following co-administration of KCZ was investigated. The Cmax was increased markedly from 59.5 to 78.7 and 131.3 ng/mL in case of OA alone, OPCH alone and OPCH with KCZ. In parallel with the Cmax, the AUC0–24h was increased from 259.6 to 306.6 and 707.7 ng h/mL, respectively. All the results obtained demonstrated that formulation of OPCH and co-administration of KCZ significantly improved the bioavailability of OA by increasing the solubility and permeability in combination with inhibiting the metabolism of OA.

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