Influences of Ferulic Acid on Pharmacokinetics of Carbamazepine in Rats: Possible Mechanism of Herb/food-drug Interactions

Abstract

Background and Objective: Carbamazepine (CBZ), an antiepileptic drug, possesses pharmacokinetic properties that make it susceptible to interaction with co-administered ingredients, such as dietaryand herbal supplements and drugs. Ferulic acid (FA) possesses anti-epileptogenic, antidepressant and antioxidant activity and is used as adjuvant therapy for epilepsy. In this study, we evaluated the effects of concomitant administration of FA on CBZ pharmacokinetics and explored a possible interaction mechanism. Materials and Methods: Rats received a single CBZ dose (80 mg kg(-1) orally [p.o.]) with and without pretreatment with FA (40 mg kg(-1) p.o. every day for 7 days). Plasma CBZ levels were determined using a reversed-phase-high performance liquid chromatography bioassay. Pharmacokinetic parameters were estimated using non-compartmental analysis. Results: Following pretreatment with FA, CBZ exhibited increases in area under concentration-time curve (AUC(0-t)) (100.32%), half-life (T-1/2) (212%) and mean residence time (MRT) (180%) compared with the group treated with CBZ alone (p<0.05). In contrast,the elimination constant (Kel), volume of distribution (Vz) and clearance (CL/F) values decreased by 69.23, 7.54 and 65.60%, respectively. The enhanced bioavailability of CBZ was accompanied by down regulated expression of cytochrome (CYP) 3A2, CYP2C11 and permeability-glycoprotein 1 (P-gp 1) (also known as multidrug resistance 1 [MDR1]) at the protein level in hepatic and intestinal tissues and increased intestinal absorption. Conclusion: The study findings indicate that metabolic inhibition of CYP450 and P-gP (MDR1) leads to a reduced rate of CBZ elimination and interactions with FA in the intestine. Therefore, patients who receive concomitant administration of FA and CBZ should be monitored carefully.