Influence of glycyrrhetinic acid on the pharmacokinetics of warfarin in rats

Abstract

1. Combination of different drugs has been widely applied in clinics in China. Both glycyrrhetinic acid (GA) and warfarin possess various pharmacological activities, the co-administration of them is becoming popular. However, the herb–drug interaction between GA and warfarin is still unknown.2. The herb–drug interaction between GA and warfarin in vivo and in vitro was studied, to clarify the effect of GA on the pharmacokinetics of warfarin and its main mechanism.3. The pharmacokinetics of intragastric administered warfarin (0.5 mg/kg) with or without GA pretreatment (100 mg/kg/day, 7 days) were investigated. The rat liver microsomes incubation systems were used to study the effect of GA on the metabolic stability of warfarin and support the in vivo pharmacokinetic data.4. The pharmacokinetic results indicated that co-administration of GA could increase the systemic exposure of warfarin, including area under the curve (48.87 ± 2.89 µg·h·mL−1 without GA versus 58.63 ± 1.90 µg·h·mL−1 with GA), maximum plasma concentration and t1/2. The metabolic stability of warfarin increased from 23.8 ± 5.9 to 41.4 ± 7.1 min with the pretreatment of GA.5. These results indicated that GA could change the pharmacokinetic profile of warfarin. The metabolism of warfarin was slowed down in rat liver and the systemic exposure increased by GA, via inhibiting the activity of CYP3A4.