Effects of Lepidium sativum, Nigella sativa and Trigonella foenum-graceum on Phenytoin Pharmacokinetics in Beagle Dogs Khalid M. Alkharfy, 1 * Fahad I. Al-Jenoobi, 2 Abdullah M. Al-Mohizea, 2 Saleh A. Al-Suwayeh, 2 Rao M. A. Khan 1 and Ajaz Ahmad 1 1 Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia 2 Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia The present work was designed to evaluate the effect of some commonly used herbs viz. garden cress (Lepidium sativum), black seed (Nigella sativa) and fenugreek (Trigonella foenum-graceum) on the disposition of phenytoin after oral administration in a dog model. Phenytoin was given orally at a dose of 50 mg, and blood samples were obtained for the determination of drug’s pharmacokinetic parameters. After a suitable washout period, animals were commenced on a specific herb treatment for one week. Garden cress treatment caused a modest increase in maximum observed concentration (C max ) and terminal half-life (T 1/2l ) of phenytoin with a reduction in clearance by 33%. The effect of black seed therapy was more drastic on drug elimination and to a lesser extent on its volume of distribution at steady state (V ss ) with a consequent reduction in systemic exposure measured by area under the curve (AUC 0-1 ) by about 87%. The effect of fenugreek therapy resembled, albeit to a lesser extent, that of black seed with a significant reduction in AUC 0-1 by ~72%. In addition, there was a 73% increase in V ss . Our findings suggest that the phenytoin disposition can be significantly altered by the concurrent consumption of tested herbal products. Copyright © 2013 John Wiley & Sons, Ltd. Keywords: herbal interaction; Lepidium sativum; Nigella sativa; phenytoin; pharmacokinetics; Trigonella foenum-graceum. INTRODUCTION Herbal remedies contain more than one active constituent such as alkaloids, flavonoids, glycosides, anthraquinones, saponins and others, which have the potential to interact with conventional drugs through different mechanisms. It has also been demonstrated that many herbal products undergo metabolism catalyzed by Cytochrome P450 (CYP) and to elicit different effects on CYP-mediated pathways including induction and inhibition (Fang et al., 2011; Han et al., 2011; Ho et al., 2011; Doehmer and Eisenbraun, 2011). For example, Ginkgo (Ginkgo biloba) has been shown to interact with many drugs. One study showed that Ginkgo’s flavonoids increase the activity of CYP3A4, which is responsible for the metabolism of the antidepressant drug trazodone to an active metabolite. This is a clinically significant inter- action as some patients with Alzheimer’s disease fell into coma after taking a combination of trazodone and Ginkgo (Izzo and Ernst, 2001). Several herbal remedies are particularly common in many Asian countries for a variety of health-related problems. For example, the seeds of Nigella sativa, commonly known as black seed or black cumin, are used in folk medicine for the treatment and prevention of a number of conditions which include asthma, diarrhea and dyslipidemia, hypertension, diabetes, inflammation, colic, headache, eczema, fever and influenza (Muhtasib et al., 2006). The important ingredients in the seed in- clude thymoquinone (TQ), nigellone, isoquinoline alka- loids and fixed oils (El-Dakhakhny, 1963; Ali and Blunden, 2003). TQ has been reported to block lipo- polysaccharide-induced phosphorylation of p38, mito- gen-activated protein kinase, extracellular-regulated kinases and nuclear factor-kappaB-p65 (Vaillancourt et al., 2011). Recent studies also showed that the Nigella sativa oil may be considered as a potential adjuvant therapy in rheumatoid arthritis (Gheita and Kenawy, 2012). Fenugreek, another commonly used herbal product, is the dried ripe seed of Trigonella foenum-graecum. The constituents of fenugreek are simple alkaloids consisting mainly of trigonelline, choline, gentianine, carpaine and saponine (Balandrin et al., 1985). It is used as nutrient and in treating kidney ailments, diabetes, cellulites and tuberculosis. Fenugreek has also been used to reduce plasma cholesterol level and enhance anti- coagulant activity (Sowmya and Rajyalakshmi, 1999; Basch et al., 2003). Enhancement of male libido has also been seen with the standardized fenugreek and its min- eral formulation (Steels et al., 2011). Garden cress is the dried ripe seed of Lepidium sativum. The major constitu- ents of garden cress seed are glucosinolates. Other consti- tuents include ascorbic acid, cucurbitacins and cardenolides (Gokavi et al., 2004; Kassie et al., 2003). The herb is used for respiratory disorders, vitamin C defi- ciency, constipation, poor immunity and as a diuretic (Nadkarni, 1954). The practitioners of Indian medicine consider the seeds are useful in dysenteric diarrhea as well as in febrile and catarrhal infections. The antidiarrheal * Correspondence to: Khalid M. Alkharfy, Pharm.D., Ph.D., Department of Clinical Pharmacy, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia. E-mail: alkharfy@ksu.edu.sa PHYTOTHERAPY RESEARCH Phytother. Res. 27: 1800 –1804 (2013) Published online 11 February 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.4947 Copyright © 2013 John Wiley & Sons, Ltd. Received 17 October 2012 Revised 16 January 2013 Accepted 16 January 2013