The characteristics and mechanism of co-administration of lovastatin solid dispersion with kaempferol to increase oral bioavailability

Abstract

1. Lovastatin shows low bioavailability (lower than 5%) after oral administration because of the poor aqueous solubility and widely metabolized by CYP3A4.

2. Lovastatin solid dispersion was designed to enhance the dissolution. The in vitro intestinal absorption study indicated an increase in the apparent permeability of different intestinal segments compared with crude lovastatin. In the range of 12.5–50 μg/ml, the absorption of both lovastatin and lovastatin solid dispersion were found to be a passive process in rat’s jejunum and ileum, but not endocytosis process. CYP3A4 inhibitor (ketoconazole) significantly increased the intestinal absorption of lovastatin and lovastatin solid dispersion. However, P-glycoprotein efflux inhibitor (verapamil) had little effect on them.

3. The absolute bioavailability of lovastatin and lovastatin acid after oral administration of lovastatin solid dispersion were increased by about 2.01-fold and 1.40-fold than that of lovastatin suspension. The oral bioavailability of lovastatin and lovastatin acid after oral administration of lovastatin solid dispersion with 10 mg/kg kaempferol (CYP3A4 inhibitor) were increased about 3.79-fold and 2.51-fold than that of lovastatin suspension, and the absolute bioavailability of lovastatin was up to 33.0%.

4. As a result, co-administration of lovastatin solid dispersion with kaempferol could be a promising delivery system to improve the oral bioavailability of lovastatin.

Keywords:

• Lovastatin
• solid dispersion
• intestinal absorption
• CYP3A4 inhibitor
• kaempferol
• bioavailability

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This project was supported by the Career Development Supporting Plan for Young and Middle-Aged Teachers in Shenyang Pharmaceutical University, China, No. (201500104).