Optimal Administration of Glycyrrhizin Avoids Pharmacokinetic Interactions With High-dose Methotrexate and Exerts a Hepatoprotective Effect

Glycyrrhizin (GZ) is widely used to treat high-dose methotrexate (MTX)-induced liver dysfunction. However, in a previous in vivo study, we showed that simultaneous administration of both drugs increased the plasma concentration of MTX and exacerbated hepatic injuries. In this study, we investigated the optimal dosing interval in rats to avoid the interaction between high-dose MTX and GZ and to demonstrate the inherent hepatoprotective effect of GZ.Male Wistar rats were treated with high-dose MTX (2,000 mg/kg) alone, with concomitant administration of 100 mg/kg GZ or GZ administered 3, 6, and 24 h before MTX administration. Plasma concentrations of MTX, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were measured.The plasma concentration and half-life of methotrexate were significantly increased after concomitant administration of GZ, or when GZ was administered 3 h before MTX administration, compared with MTX alone, increasing hepatic enzyme levels. However, when GZ was administered 6 and 24 h before MTX administration, the levels were not significantly different from those of MTX alone and showed a tendency to decrease MTX-induced liver injury. These results suggest that the pharmacokinetic interaction between GZ and MTX could be avoided and the hepatoprotective effect of GZ could be achieved by an optimal dosing regimen, using the half-life of GZ as an indicator.When using high-dose MTX in combination with GZ, the administration intervals should be considered to avoid unwanted interactions and to achieve the GZ hepatoprotective effect.