CARBAMAZEPINE KINETICS WITH PIPERINE IN EPILEPSY 1281 Copyright © 2009 John Wiley & Sons, Ltd. Phytother. Res. 23, 1281–1286 (2009) DOI: 10.1002/ptr Copyright © 2009 John Wiley & Sons, Ltd. PHYTOTHERAPY RESEARCH Phytother. Res. 23, 1281–1286 (2009) Published online 12 March 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/ptr.2676 Pharmacokinetic Interaction of Single Dose of Piperine with Steady-state Carbamazepine in Epilepsy Patients Smita Pattanaik 1 , Debasish Hota 1 , Sudesh Prabhakar 2 , Parampreet Kharbanda 2 and Promila Pandhi 1 * 1 Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh-160012, India 2 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh-160012, India Piperine, the active principle of piper species, is commonly used as a spice and adjuvant in various traditional systems of medicine. It has been known as a bioavailability-enhancer. The present study aimed at evaluating the effect of piperine on the steady-state pharmacokinetics of a single dose of carbamazepine in poorly controlled epilepsy patients on carbamazepine monotherapy. Patients (n = 10 each) receiving either 300 mg or 500 mg dose of carbamazepine twice daily were selected. After administration of carbamazepine, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h. Subsequently, piperine (20 mg p.o.) was administered along with carbamazepine and samples were collected similarly. The pharmacokinetic parameters were com- pared by Students t-test. Piperine significantly increased the mean plasma concentrations of carbamazepine at most of the time points in both dose groups. There was a significant increase in AUC 0-12hr (p < 0.001), average C ss (p < 0.001), t 1\2el (p < 0.05) and a decrease in K el (p < 0.05), in both the dose groups, whereas changes in K a and t 1\2a were not significant. Cmax (p < 0.01) and t max (p < 0.01) were increased significantly following piperine administration in the 500 mg dose group; however, these parameters were not significant in the lower dose group. Piperine could significantly enhance the oral bioavailability of carbamazepine, possibly by decreasing the elimination and/or by increasing its absorption. Copyright © 2009 John Wiley & Sons, Ltd. Keywords: piperine; carbamazepine; oral bioavailability; pharmacokinetics; interaction. Received 31 December 2007 Revised 8 July 2008 Accepted 8 July 2008 * Correspondence to: Dr Promila Pandhi, Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh- 160 012, India. E-mail: ppandhi17@hotmail.com in many Ayurvedic preparations (Anand, 1990). Stud- ies have demonstrated that piperine inhibits several constitutive as well as inducible cytochrome P 450 (CYP 450) activities in vitro and in vivo (Atal et al., 1985). It has been postulated that use of piperine from piper species in routine daily Indian diet and traditional herbal formulations might have been responsible for the enhancement of drug bioavailability consequent to modulation of drug metabolism (Johri and Zutsi, 1982; Singh et al., 1986; Reen et al., 1996). Several clinical and experimental studies have demonstrated the in- crease in the bioavailability of many structurally and therapeutically diverse drugs, such as rifampicin, pyrazinamide propranolol, theophylline, nimesulide, phenytoin, and other nutrients such as beta-carotene and vitamins (Zutsi et al., 1984; Bano et al., 1987; Zutsi, 1989; Bano et al., 1991; Gupta et al., 2000; Velpandian et al. , 2001; Pattanaik et al., 2006). Piperine has been shown to enhance the plasma CBZ concentrations in rabbits (Karan et al., 1999). Extensive study of the literature could not reveal any report of interaction between piperine and CBZ in healthy men or epileptic patients. Hence the present study was planned to evaluate the effect of piperine on the steady-state pharmacokinetics of CBZ in epilepsy patients on monotherapy. PATIENTS AND METHODS Patients. Adult epileptic patients of either sex, between 20 and 45 years of age were screened in the neurology INTRODUCTION Pharmacotherapy is the mainstay of treatment for most epilepsy patients. The overall goal of antiepileptic drug (AED) therapy is to completely suppression of seizure occurrence without any significant adverse side effects, preferably with a single drug on a simple dosing sched- ule. Despite the availability of several newer AEDs, carbamazepine (CBZ) still enjoys the status of frontline therapy for partial seizures and alternative therapy for secondarily generalized tonic clonic seizures (Lowenstein, 2005). Overall, it is equally effective as the currently marketed drugs and is significantly less expensive compared to the newer agents (Roger and Brian, 2007). CBZ has also shown good clinical effec- tiveness in the treatment of trigeminal neuralgia and bipolar disorders (Barry and William, 2006). Piperine (trans-trans isomer of 1- piperoyl piperidine) is the active principle and main ingredient of piper species. Dried fruits of long pepper (Piper longum Linn.), black pepper (Piper nigrum Linn.) and dried rhizomes of ginger (Zingiber officinalis Rosc.) are com- monly used as spices and adjuvants in various tradi- tional systems of medicine. The crude powder of each in equal proportions is used in Ayurveda under the name of ‘Trikatu’ and has been reported to be present