Carbamazepine Shows Plasma and Tissue Pharmacokinetic Interactions with Ajuga bracteosa Extract in Rats

Abstract

Carbamazepine (CBZ) is the first-line anticonvulsant drug with a narrow therapeutic index (NTI) and is a substrate for CYP3A4 and MRP-2. Ajuga bracteosa (AB), family Lamiaceae is widely used to treat epilepsy, gastric diseases, and protects against liver damage in folk. It contains bioactive metabolites, which are powerful inhibitors of CYP3A4, CYP3A5, CYP19, CYP2C19 enzymes and P-gp transporter. Concomitant use of NTI drugs with herbs, like AB increase the chances of herb-drug interactions (HDIs). This study was aimed to analyze the Ajuga bracteosa crude extract (ABCE) and to investigate its effect on the pharmacokinetics of CBZ in rats. In the pre-treatment study, rats received ABCE (1000\u2009mg/kg) orally for 14 days, followed by a single dose of CBZ (80\u2009mg/kg) on the 15th day. In the co-administration study, single doses of ABCE and CBZ were administered concomitantly in one session. All the doses were administered in 0.5% carboxymethylcellulose (CMC) as a vehicle. HPLC analysis showed that extract contained 1.3\u2009mg/g ursolic acid, 2.1\u2009mg/g sitosterol and 2.9\u2009mg/g stigmasterol. Non-compartmental pharmacokinetic analysis showed an increase in Cmax, AUC0-∞, MRT, and t1/2 with a decrease in tmax, Vd and Cl of CBZ in both, pre-treated and co-administered groups vs controls. An increase in CBZ concentration in liver tissue of both pre-treated as well as co-administered animals was observed as compared to control. The above results suggested possible HDIs between AB and CBZ thus, may warrant CBZ dose adjustment in epileptic patients with simultaneous administration of AB or its products.