The Laryngoscope V C 2012 The American Laryngological, Rhinological and Otological Society, Inc. Effect of Grapefruit Juice on Bioavailability of Montelukast Cemal Cingi, MD; Sema Zer Toros, MD; Melek Kezban Gu ¨ rbu ¨ z, MD; Iskender Ince, MD; Hamdi Cakli, MD; Nagehan Erdogmus, MD; Ercument Karasulu, MD; Ercan Kaya, MD Objectives/Hypothesis: The aim of this study was to investigate possible interactions between grapefruit juice and montelukast for up to 4 hours. Study Design: A prospective, crossover study with 23 healthy volunteers was performed in two sessions. Methods: In the first session, volunteers were treated with oral montelukast 10 mg once daily with 250 ml water. After a 10-day washout period, the same volunteers were treated with 10 mg montelukast with 250 ml grapefruit juice. Blood sam- ples were collected 2, 3, and 4 hours after drug administration and kept at 80  C after both applications. Plasma samples were analyzed for montelukast concentration. Results: The mean plasma concentration of montelukast across all time intervals was significantly greater (P ¼ 0.0001) for those given grapefruit juice (517, 484, and 440) versus those treated with water (366, 356, and 292). Moreover, with respect to the time the sample was collected, there was no significant difference (P ¼ 0.13) in the mean total plasma concen- tration up to 4 hours after montelukast ingestion for either group. There was a significant difference between the groups according to the area under curve with regard to marginal and cumulative values for all different time intervals (P < 0.05). Conclusions: Plasma concentration of montelukast was higher when administered with grapefruit juice, as compared to with water. This may have been due to the effect of grapefruit on liver metabolism of montelukast and the cytochrome P450 system. Key Words: Grapefruit juice, montelukast, allergy, bioavailability, asthma, drug interactions. Level of Evidence: 2b. Laryngoscope, 123:816–819, 2013 INTRODUCTION It has been reported in pharmacological literature that, when any two active ingredients are combined, the interaction can potentially cause alterations in the mo- lecular structure and pharmacokinetic properties of the interacting ingredients. This type of drug–drug interac- tion not only affects the bioavailability of the ingredients but also their beneficial and harmful effects. One such example of this is the effect of grapefruit juice on the plasma levels of various drugs. In previous studies, grapefruit juice has been shown to augment the bioavail- ability of several drugs, increasing both the beneficial and adverse effects of the medication, despite the grape- fruit juice being consumed several hours beforehand. 1 Previously studied drugs include triazolam, midazolam, terfenadine, cyclosporine, and dihydropyridine calcium channel blockers, including felodipine, nifedipine, nitren- dipine, and nisoldipine. 2 The bioactive chemical compounds (furanocoumarins) present in grapefruit degrade and inhibit intestinal cytochrome P450 (CYP3A4) activity, which regulates drug metabolism. In fact, CYP3A4 levels have been shown to be reduced by as much as 47% 4 hours after grapefruit juice ingestion. 3 We designed a study to investigate the effect of grapefruit juice on the bioavailability of montelukast, a leukotriene receptor antagonist with proven efficacy in asthma and allergic rhinitis, metabolism of which is pri- marily though the CYP450 system. 4 Although the scientific literature has some published reports on the effectiveness of montelukast in combination with antihist- amines and steroids, 4–6 the data regarding the drug and food interactions for montelukast are scarce. Based on previous studies, we hypothesized that that the plasma level of montelukast would be higher in individuals taking the drug with grapefruit juice, as compared to with water. MATERIALS AND METHODS The study was a prospective, parallel group study con- ducted between April 1, 2011, and April 20, 2011, at the Department of Ear, Nose, and Throat, University of Osmangazi, Turkey. Approval for the study was obtained from the Ethics Committee, and informed consent was obtained from each par- ticipant upon enrollment. Study Population The study group comprised 23 healthy volunteers (12 male, 11 female) aged 22 to 25 years. Patients with concomitant illness (malignancy, hepatic, psychiatric, endocrine, or other major sys- temic diseases); drug users and smokers were excluded. From the Department of Otorhinolaryngology (C.C., M.K.G., H.C., N.E., E.K.), Osmangazi University, Medical Faculty, Eskisehir; the Department of Otorhinolaryngology/Head and Neck Surgery (S.Z.T.), Haydarpas a Numune Research and Education Hospital, Istanbul, Center for Drug Research & Development and Pharmacokinetic Applications (I.I., E.K.I.I., E.K.X), Ege University, 35100 Bornova, _ Izmir, Turkey. Editor’s Note: This Manuscript was accepted for publication August 3, 2012. The authors have no funding, financial relationships, or conflicts of interest to report. Send correspondence to Sema Zer Toros, M.Saadettin Sokak, Saa- det Apartmanı, No: 3 D: 4, Ortak€ oy /Bes iktas , Istanbul, Turkey, PK: 34347. E-mail: semazertoros@yahoo.com DOI: 10.1002/lary.23700 Laryngoscope 123: April 2013 Cingi et al.: Effect of Grapefruit Juice on Bioavailability of Montelukast 816