Effects of Glycyrrhizic Acid on Solubility, Pharmacokinetics and Liver Distribution of Osthole in Rats

  OBJECTIVE  To investigate the potential of glycyrrhizic acid (GL) to improve the solubility and bioavailability of osthole (Ost), and to explore the underlying mechanism of the potential solubility and pharmacokinetic interactions.

  METHODS  Male Sprague-Dawley rats were orally given osthole (20 mg·kg^-1) alone or with glycyrrhizic acid (45 mg·kg^-1). Blood and liver samples were collected at specific time points and determined by an LC-MS/MS method. The effect of glycyrrhizic acid on the solubility of osthole, and physical characterizations, including X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectroscopy, were performed to reveal the mechanism of the solubilization of GL. In addition, bidirectional transport study using Caco-2 cell monolayer model was employed to study the effects of glycyrrhizic acid and its active metabolite glycyrrhetinic acid (GC) on the absorption of osthole. In incubation studies, rat enterocyte S9 and liver S9 were used to explore the potential effect of GL and GC on the metabolism of osthole.

  RESULTS  The results of pharmacokinetics in rats showed that co-administration of glycyrrhizic acid could significantly increase the AUC of osthole as compared with osthole administered alone. The results of rat liver tissue samples indicated that glycyrrhizic acid increased the distribution of osthol in liver tissue. Solubility study found that glycyrrhizic acid could significantly enhance the solubility of osthole in water due to the decreased crystallinity of osthole and the formation of hydrogen bonding between Ost and GL. Caco-2 cell monolayer model demonstrated that neither GL nor GC could enhance osthole absorption. Further in vitro incubation study revealed that there was little metabolic interaction between osthole and GL or GC in phaseⅠmetabolism.

  CONCLUSION  Increased AUC and liver concentration of osthole are probably due to the increased solubility of osthole by GL. The current study has significant implications for further investigation on the potential combination use of natural solubilizing agent GL and drugs with solubility as the rate-limiting step to absorption from the gastrointestinal tract.