Concomitant Use of High-dose Methotrexate and Glycyrrhizin Affects Pharmacokinetics of Methotrexate, Resulting in Hepatic Toxicity.

Abstract

High-dose methotrexate is a therapy for acute leukemia, malignant lymphoma, and osteosarcoma. Glycyrrhizin has been used to treat hepatic dysfunction caused by high-dose methotrexate. However, few studies have investigated the interaction between glycyrrhizin and high-dose methotrexate. Male Wistar rats were treated with high-dose methotrexate (500 or 1,000 mg/kg) alone, or with co-administration of 100 mg/kg glycyrrhizin. Plasma concentrations of methotrexate, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were measured. At both methotrexate doses, the blood concentration of methotrexate was significantly increased and total clearance was significantly reduced using co-administration of glycyrrhizin compared with methotrexate alone, which led to increased levels of hepatic enzymes. These results suggest that glycyrrhizin significantly increases the plasma level and delays the clearance of methotrexate, resulting in hepatic toxicity. The concomitant use of methotrexate and glycyrrhizin should be considered with caution.