Herb-drug interaction between Dahuang-Gancao decoction and clozapine: A pharmacokinetic study in rats

Dahuang-Gancao decoction (DGD) comprises Rhei Radix et Rhizoma and Glycyrrhizae Radix et Rhizoma at ratio of 4:1, which is usually applied for relieving clozapine-induced constipation in clinical practice. However, the herb-drug interactions involving antipsychotics with narrow therapeutic range have rarely been reported. We investigated a potential pharmacokinetic-based interaction between DGD and clozapine based on in vitro and in vivo studies. Rats received a single injection of clozapine (5 mg/kg, i.v. ,) 30 min after pretreatment with DGD ( p.o. ) for 3 days or 14 days. The concentrations of clozapine and its metabolites in rat plasma were measured by high-performance liquid chromatography-tandem mass spectrometry. The effects of DGD on protein expression of cytochrome P450 (CYP450) in vivo and the binding of plasma proteins to clozapine in vitro were determined. After 3-day pretreatment with DGD, there were no significant changes in the pharmacokinetics of clozapine or its metabolites. A significant increase in certain pharmacokinetic parameters of clozapine was observed after 14-day pretreatment with DGD. Protein expression of CYP1A2 was inhibited via multiple dosage of DGD in time-dependent manner. The plasma protein binding rate in various concentrations of clozapine was reduced significantly in vitro after DGD therapy. The effects upon pharmacokinetics of clozapine after DGD pretreatment could be attributed to inhibition of CYP1A2 expression and a decrease in plasma protein binding. Hence, caution must be applied to some drugs with a narrow therapeutic index to avoid the potential risk of herb-drug interactions in clinical practice.