Effects of Grapefruit and Pomegranate Juices on the Pharmacokinetic Properties of Dapoxetine and Midazolam in Healthy Subjects

Transcription

1 Eur J Drug Metab Pharmacokinet DOI /s ORIGINAL RESEARCH ARTICLE Effects of Grapefruit and Pomegranate Juices on the Pharmacokinetic Properties of Dapoxetine and Midazolam in Healthy Subjects Khaled S. Abdlekawy 1 Ahmed M. Donia 2 Fawzy Elbarbry 3 Springer International Publishing Switzerland 2016 Abstract Background The package leaflet for dapoxetine, an effective treatment for premature ejaculation, includes a strict warning against coadministration with drugs or herbal remedies that strongly induce or inhibit the activity of Cytochrome P450 (CYP) 3A4 enzyme. Objective To assess the effects of multiple daily consumption of grapefruit juice (GFJ) and pomegranate juice (PJ) on the pharmacokinetics of dapoxetine, we conducted an open-label, three-way crossover study in 12 healthy subjects using midazolam as a probe substrate for CYP3A4. Methods Participants received a single oral dose of dapoxetine (60 mg) and midazolam (7.5 mg) after pretreatment with 250 ml of either water, undiluted GFJ, or PJ for three consecutive days. All subjects were monitored for adverse effects during the study period. Results Compared to pretreatment with water, GFJ increased the area under the plasma concentration time curve from time zero to infinity (AUC 0? ) and peak plasma concentration (C max ) of dapoxetine by 60 and 80 %, respectively, and prolonged its elimination halflife (t 1/2 ) by 43 %. Similar effects of GFJ on the pharmacokinetics of midazolam were observed with a significant increase in AUC 0? (75 %), C max (40 %), and t 1/2 (92 %). Slight but not statistically significant & Fawzy Elbarbry Fawzy.elbarbry@pacificu.edu Faculty of Pharmacy, Kafrelsheikh University, Kafr el-sheikh, Egypt Faculty of Pharmacy, Tanta University, Tanta, Egypt School of Pharmacy, Pacific University, 222 SE 8th Ave., Hillsboro, OR 97123, USA changes were observed in the pharmacokinetics of dapoxetine and midazolam after pretreatment with PJ. Time to reach C max (T max ) did not differ among the three phases. Conclusion These results suggest that GFJ increases the extent of absorption and reduces clearance of dapoxetine possibly by inhibition of both intestinal and hepatic CYP3A4, whereas PJ has little effect on dapoxetine pharmacokinetics. Although the impact of GFJ on the pharmacokinetics of dapoxetine was mild, a great caution should be considered when they are concomitantly administered. Key Points Consumption of grapefruit juice for three consecutive days results in a mild to moderate increase in plasma concentration and AUC of dapoxetine and midazolam. Inhibition of intestinal and hepatic CYP3A4 may explain the observed effect of grapefruit juice on the pharmacokinetics of dapoxetine and midazolam. Consumption of pomegranate juice for three consecutive days did not produce any significant changes in the pharmacokinetics of dapoxetine or midazolam. Patients taking dapoxetine should experience caution when consuming grapefruit juice, but not pomegranate juice.

2 K. S. Abdlekawy et al. 1 Introduction Male sexual dysfunction is a common disorder that appears to be a consequence of a wide range of physical and psychological conditions. Sexual dysfunction in males includes premature ejaculation (PE), erectile dysfunction and sexual desire disorder. From an epidemiological perspective, PE has been reported as the most common male sexual symptom with global prevalence rates estimated at approximately 30 %, especially in USA [1]. Dapoxetine, a short-acting selective serotonin reuptake inhibitor, is an effective and safe treatment for PE that represents a major advance in sexual medicine. An integrated analysis of five trials showed that the PE profile measures improved significantly with dapoxetine [2]. It is absorbed with a T max of h, and elimination is biphasic with an initial halflife (t 1/2 ) of 1.4 h and a terminal t 1/2 of 17 h [3]. Dapoxetine is metabolized by multiple Cytochrome P450 (CYP) isoenzymes, mainly CYP3A4 and CYP2D6. Both plasma concentration and area under the curve (AUC) are dosedependent up to 100 mg [3]. Limited studies are available for dapoxetine pharmacokinetic interactions, especially with herbal remedies. According to the World Health Organization (WHO), herbal medicines are getting significant attention in global health discussions, and it can be safely presumed that traditional herbal medicines and other alternative therapies will play a significant role in future strategies to alleviate and treat chronic illnesses. Because herbal supplements are not subject to the same regulations as prescription drugs, there are several risks associated with their use, especially possible herb drug interactions [4]. Several herbal remedies have been shown to modulate drug metabolizing enzymes and transporters, leading to altered pharmacokinetic and potentially negative pharmacodynamic outcomes. Whereas many phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been undetermined and requires investigations [5]. Grapefruit juice (GFJ) is a common beverage due to its reported cardiovascular and cancer chemoprevention benefits [6]. Several in vitro and animal studies have reported that GFJ can significantly augment oral bioavailability and inhibit elimination of drugs that undergo first-pass effect by intestinal CYP3A4 enzyme [7]. This effect of GFJ is especially relevant because more than 20 % of Americans drink it with breakfast, when medications are commonly administered [8]. Since 1993, grapefruit juice drug interactions have received extensive interest from the scientific, medical, and regulatory communities [9]. Despite the known health benefits of grapefruit juice, its consumption in combination with drugs requires great caution and patient education by health care professionals [10]. A single glass of grapefruit juice or one whole grapefruit has sufficient potency to cause a clinically significant pharmacokinetic interaction with a dose-dependent magnitude and significance [11]. Pomegranate fruit is commonly eaten around the world, and has been used in folk medicine for a wide variety of therapeutic purposes [12]. It has been reported that pomegranate contains certain species of flavonoids and anthocyanins in its seed oil and juice [13]. Recently, there are some reports on the inhibition of CYP3A activities by pomegranate juice (PJ). Therefore, it is important to assess the interaction between PJ and CYP3A4 substrates in clinical practice. Drug drug interactions involving CYP3A4 are of particular importance because of the large number of marketed drugs that are metabolized by this enzyme. Multiple probe substrates are often used for CYP3A4 drug interaction studies. Clinically, midazolam is the ideal standard probe for studying CYP3A4 interaction [14]. Patients receiving dapoxetine for the treatment of PE could potentially take grapefruit juice or pomegranate juice as a common beverage. As dapoxetine undergoes extensive metabolism by CYP3A4, there is a potential of herb drug interaction if it is co-administered with grapefruit and/or pomegranate juice due to the reported inhibitory effect of these fruit juices on CYP3A4. Therefore, this study aimed to investigate the pharmacokinetic interaction of dapoxetine with GFJ and PJ in male subjects using midazolam as CYP3A4 probe. 2 Patients and Methods 2.1 Subjects Twelve healthy males were included in the study. The subjects were recruited and studied at the Pharmaceutical Research Center of Faculty of Pharmacy, Tanta University, Egypt, from April 2015 to July The study protocol was approved by the ethics committee of Tanta University in accordance with the Declaration of Helsinki. All subjects provided written informed consent before participation. All subjects were ascertained to be healthy by medical history, physical examination, and routine laboratory tests. 2.2 Evaluation of Safety Adverse events (AEs) were monitored throughout the study. All observed AEs were recorded by the principal investigator, including severity and potential relationship to dapoxetine or midazolam. Safety was also assessed by physical examination, clinical laboratory tests and measuring vital signs.

3 Modulation of Dapoxetine s Pharmacokinetics by Grapefruit and Pomegranate Juices 2.3 Study Design A random three-period intra-individual crossover single dose study was employed. Participants abstained from taking any drug for at least 3 days before and during the study period. The subjects ingested 250 ml of water, 250 ml of GFJ, or 250 ml of PJ for 2 days. On day 3, each volunteer received dapoxetine tablet 60 mg, and midazolam tablet 7.5 mg with 250 ml of water, 250 ml of GFJ, or 250 ml of PJ. A 1-week washout period was allowed between each intervention (Fig. 1). All subjects fasted overnight for 8 h before administration of dapoxetine and midazolam, and received a standardized meal 4 h after. No smoking was allowed during the blood sampling period. It should be noted that a 7-day wash-out period was selected based on the published dapoxetine half-life of 17 h. Even with expected effects of GFJ or PJ on the elimination kinetics of dapoxetine, we believe that 7 days should be enough to avoid any dapoxetine carry over into the next study period. Additionally, the sample size was set to 12 subjects for each phase to be sufficient to detect a 20 % change in the pharmacokinetic parameters with a power of 80 % (a-level, 5 %) [15, 16]. 2.4 Blood Sampling In each study period, 3-ml venous blood samples were collected from an indwelling catheter placed in an antecubital vein or by direct venipuncture into heparinized tubes at predose (0 h) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 5, 8, 12, 24, and 48 h after dapoxetine and midazolam administration. Plasma was obtained by centrifugation and stored at -20 C until HPLC assay. 2.5 Determination of Dapoxetine and Midazolam by HPLC Plasma samples were analyzed for dapoxetine and midazolam in one run using a validated HPLC (Shimadzu HPLC LC2010HT, Shimadzu Corporation, Japan) method developed in the laboratory of Pharmaceutical Research Center of Faculty of Pharmacy, Tanta University, Egypt. Clean test tubes were spiked with 50 ll of the internal standard solution (5 lg/ml alprazolam in methanol) and the methanol was left to evaporate in a water bath adjusted at 50 C. To these tubes, 0.5 ml of the collected plasma samples was added and the tube contents were vortex mixed for 3 min. The plasma samples already spiked with the internal standard were extracted with 4 ml of ether followed by vortex mixing for 3 min. After centrifugation for 10 min, the ether layer was transferred to a clean test tube and was evaporated in a water bath at 50 C. The residue was dissolved in 150 ll of the mobile phase and 50 ll of the resulting solution was injected into the HPLC. The mobile phase consisted of methanol and 50 mmol ammonium dihydrogen phosphate buffer (ph adjusted to 2.5 with phosphoric acid) at a ratio 50:50. Separation was achieved at ambient temperature using column C 8 Fig. 1 Schematic diagram of the study design. GFJ grapefruit juice, PJ pomegranate juice

4 K. S. Abdlekawy et al. pharmacokinetic values were performed using ANOVA with Tukey test. p values \0.05 were considered significant. 3 Materials Fig. 2 A representative HPLC chromatogram of a human plasma sample containing dapoxetine, midazolam, and the internal standard alprazolam, obtained following a single oral administration of 60 mg dapoxetine and 7.5 mg midazolam ( mm I.D) at a flow rate of 1.2 ml/min. The column effluent was monitored by UV detector at 220 nm. The retention times for dapoxetine, alprazolam, and midazolam were 3.6, 6.3, and 8.1, respectively (Fig. 2). To construct calibration curves, blank human plasma was spiked with the internal standard and known amounts of dapoxetine and midazolam to produce standard solutions with concentrations in the range of and lg/l, respectively. The concentrations of dapoxetine and midazolam in the study samples were determined from the calibration curves. The method was validated using blank human plasma and was shown to be accurate ( %) and precise (CV % less than 16 %) in quantifying all standards and quality control samples. 2.6 Pharmacokinetic and Statistical Calculations The plasma concentration time profiles of dapoxetine and midazolam of each subject were analyzed by a non-compartmental method using WinNonlin software (v 6.1; Pharsight Corporation, Mountain View, CA, USA). Pharmacokinetic values for peak concentration (C max ) and time to C max (T max ) were taken directly from the observed data. Individual concentration versus time profiles were plotted, and the terminal elimination rate constant (k e ) was determined by the log-linear regression of at least three data points judged to be in the terminal phase. The terminal half-life (t 1/2 ) was determined from the elimination rate constant using the equation (0.693/k e ). Area under curve from time zero to infinity (AUC 0? ) was determined by the trapezoidal method for the detected values and subsequent extrapolation to infinity. The apparent oral clearance (CL/ F) was obtained as dose/auc 0?. Descriptive statistics, including geometric mean and associated 90 % confidence interval (CI), were used to summarize the pharmacokinetic parameters of dapoxetine and midazolam. Statistical comparisons of the estimated Dapoxetine 60 mg tablets (Joypox ) were obtained from South Egypt for Drug Industries Co. (SEDICO), Ismailia, Egypt. Midazolam 7.5 mg tablets (Mediathetic ) were obtained from Amoun Pharmaceutical Company (Cairo, Egypt), and alprazolam was obtained from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA). Pure grapefruit juice (Rauch International, Rankweil, Austria), and pure pomegranate juice (Ionis For Food Industries, Cairo, Egypt) were purchased from the local market. Acetonitrile, methanol, ammonium dihydrogen phosphate, and phosphoric acids were purchased from Honeywell Specialty Chemicals Seelze (Seelze, Germany). All solvents were of HPLC grade. Diethyl ether of analytical grade was obtained from Honil Limited (London, UK). 4 Results A total of 12 subjects were enrolled in this study. The average age of these subjects was 41 years (range years) and the average weight was 85 kg (range kg). None of the subjects had clinically significant changes in vital signs or ECG during the study period (data not shown). However, five participants (1 in the 1st phase, 2 in the 2nd phase, and 2 in the 3rd phase) who were pretreated with GFJ reported adverse effects including severe headache, fatigue, and dizziness. These effects, however, were mild-to-moderate in severity and resolved within a few hours without any therapeutic intervention. 4.1 Effect of GFJ and PJ on the Pharmacokinetics of Dapoxetine Dapoxetine was rapidly absorbed after oral administration reaching a maximum plasma concentration in about 1.0 h. There was no observed effect on the rate of absorption of dapoxetine following administration of either GFJ or PJ as indicated by non-significant changes in T max with geometric mean ratios of 97 and 98 %, respectively. The mean plasma concentration time profiles of a single 60 mg dose of dapoxetine after three consecutive days of pretreatment with water, GFJ, or PJ are shown in Fig. 3. Compared to pretreatment with water, GFJ resulted in a significant increase in dapoxetine s extent of absorption. Specifically, the geometric mean ratios for AUC 0? and C max were 156 % (90 % CI, %) and 177 % (90 % CI,

5 Modulation of Dapoxetine s Pharmacokinetics by Grapefruit and Pomegranate Juices Fig. 3 Mean ± SD plasma concentration time profile of dapoxetine following a single 60 mg oral dose and pretreatment with water, grapefruit juice (GFJ), or pomegranate juice (PJ) once daily for %), respectively. On the other hand, consumption of PJ resulted in a non-significant increase in AUC 0? and C max of dapoxetine as demonstrated by 90 % CI of the geometric mean ratios in the accepted interval of %. Additionally, consumption of GFJ resulted in significant changes in dapoxetine s elimination kinetics. Specifically, the geometric mean ratios for CL/F and t 1/2 were 52 % (90 % CI, %) and 181 % (90 % CI, %), respectively. Similar to the observed effects on dapoxetine s absorption kinetics, PJ did not cause any significant changes in these elimination pharmacokinetic parameters as evident by geometric mean ratios for CL/F and t 1/2 of 99 % (90 % CI, %) and 91 % (90 % CI, %), respectively. Table 1 summarizes the geometric mean ratios and related 90 % CI for the pharmacokinetic parameters of dapoxetine with and without administration of GFJ or PJ. 4.2 Effect of GFJ and PJ on the Pharmacokinetics of Midazolam The mean plasma concentration time profiles of a single 7.5 mg dose of midazolam after three consecutive days of pretreatment with water, GFJ, or PJ are shown in Fig. 4. Midazolam was rapidly absorbed after oral administration, reaching a maximum plasma concentration in about 0.5 h. Neither GFJ nor PJ treatments caused any significant changes in midazolam s rate of absorption as indicated by non-significant changes in T max with geometric mean ratios 3 days. a Conc. values plotted on a linear scale, b conc. values plotted on a logarithmic scale of 98 and 103 %, respectively. Only coadministration of GFJ resulted in significant increases in extent of absorption of midazolam as indicated by 75 and 40 % increase in geometric means of AUC 0? and C max, respectively. No significant changes in midazolam AUC 0? and C max were observed after the intake of PJ. Very similar to the impact of GFJ on dapoxetine s elimination kinetics, clearance of midazolam was also significantly affected as reflected by 85 % increase and 47 % decrease in geometric means of t 1/2 and CL/F, respectively. Pomegranate juice, on the other hand, did not cause any significant changes in midazolam s elimination kinetics. Table 2 illustrates the geometric mean ratios and corresponding 90 % CI for the pharmacokinetic parameters of midazolam with and without administration of GFJ or PJ. 5 Discussion The present study was undertaken to investigate the potential effect of GFJ and PJ on the pharmacokinetics of dapoxetine. The results of this study show that consumption of GFJ, but not PJ, increases the extent, but not the rate of absorption of dapoxetine as reflected by a significant increase in both AUC 0? and C max values. In addition, the current study showed a significant prolongation in t 1/2 and reduction of CL/F of dapoxetine only with GFJ administration. Our study also demonstrated a similar effect of GFJ

6 K. S. Abdlekawy et al. Table 1 Geometric mean ratio for dapoxetine pharmacokinetic parameters after a single oral dose (60 mg) with and without coadministration of grapefruit juice (GFJ) or pomegranate juice (PJ) to 12 healthy male subjects Pharmacokinetic parameters Water phase GFJ phase PJ phase GM a GM a GMR b (90 % CI) GM a GMR c (90 % CI) AUC 0? lg h/l) ( ) ( ) C max (lg/l) ( ) ( ) T max (h) ( ) ( ) t 1/2 (h) ( ) ( ) CL/F (l/h) ( ) ( ) AUC 0? area under the concentration time curve from time 0 to infinity, C max maximum plasma concentration, T max time required to achieve C max, t elimination half-life, CL/F apparent oral clearance a GM geometric mean b GMR geometric mean ratio (GFJ/water) c GMR geometric mean ratio (PJ/water) Fig. 4 Mean ± SD plasma concentration time profile of midazolam following a single 7.5 mg oral dose and pretreatment with water, grapefruit juice (GFJ), or pomegranate juice (PJ) once daily for 3 days. a Conc. values plotted on a linear scale, b conc. values plotted on a logarithmic scale on oral bioavailability and clearance of midazolam, a specific probe substrate for CYP3A4. Therefore, we postulate that the pharmacokinetic interactions between dapoxetine and GFJ may be attributed to inhibition of intestinal and hepatic CYP3A4 enzyme. To our knowledge, this is the first study to demonstrate the effect of regular consumption of GFJ and PJ on the pharmacokinetics of dapoxetine. A plethora of information derived from several in vitro and in vivo studies have established that the significant clinical drug interactions with GFJ are primarily attributed to its potent inhibitory effect on intestinal and hepatic CYP3A4. Several studies have reported that the furanocoumarins bergamottin and 6 0,7 0 -dihydroxybergamottin, and the flavonoid naringenin, are the main compounds responsible for inhibition of CYP3A4 and possibly P-glycoprotein (p-gp) [17]. Although inhibition of p-gp would be an acceptable mechanism for the enhanced absorption of dapoxetine after consumption of GFJ, it is currently not know if dapoxetine is a p-gp substrate. Additionally, inhibition of p-gp only does not explain the effect on clearance of dapoxetine. Since 1993, several studies have shown significant interactions between GFJ and drugs metabolized by CYP3A4 [18 22]. Paine et al. reported that unlike other known CYP3A inhibitors, normal consumption of GFJ only inhibits CYP3A in the enterocyte cells lining the small intestine while hepatic CYP3A activity remains unaffected

7 Modulation of Dapoxetine s Pharmacokinetics by Grapefruit and Pomegranate Juices Table 2 Geometric mean ratio for midazolam pharmacokinetic parameters after a single oral dose (7.5 mg) with and without coadministration of grapefruit juice (GFJ) or pomegranate juice (PJ) to 12 healthy male subjects Pharmacokinetic parameters Water phase GFJ phase PJ phase GM a GM a GMR b (90 % CI) GM a GMR c (90 % CI) AUC 0? (lg h/l) ( ) ( ) C max (lg/l) ( ) ( ) T max (h) ( ) ( ) t 1/2 (h) ( ) ( ) CL/F (l/h) ( ) ( ) AUC 0? area under the concentration time curve from time 0 to infinity, C max maximum plasma concentration, T max time required to achieve C max, t elimination half-life, CL/F apparent oral clearance a GM geometric mean b GMR geometric mean ratio (GFJ/water) c GMR geometric mean ratio (PJ/water) [23]. However, our study shows that apparent oral clearance (CL/F) of dapoxetine has been significantly reduced by GFJ administration. This reduction may be attributed to inhibition of clearance and/or enhancement of oral bioavailability. Prolongation of the elimination half-life (t 1/ 2) is a strong evidence of inhibiting the systemic clearance of dapoxetine, which is mostly mediated by hepatic CYP3A4 [3]. Additionally, the reported increase in both AUC 0? and C max indicates a significant increase in extent of absorption and oral bioavailability. As dapoxetine undergoes a significant first-pass effect by the intestinal CYP3A4, inhibition of this effect by GFJ may explain the enhanced bioavailability. Therefore, we believe that inhibition of intestinal and hepatic CYP3A4 is the primary mechanism behind the observed enhancement of absorption and decrease in elimination of dapoxetine in this study. This conclusion was also confirmed by similar changes in absorption and elimination kinetics of midazolam, a specific probe substrate for CYP3A4. Although the effect of GFJ was mild-to-moderate and no significant clinical effects were observed in our study, a great caution should be exercised when co-administering dapoxetine with GFJ. Several in vitro and animal studies have reported that components of PJ inhibit CYP3A4 activity. For example, Hidaka et al. demonstrated significant inhibition of midazolam hydroxylase as well as carbamazepine epoxidation activity in human liver microsomes and rats after consumption of PJ [24]. The authors of this study reported that oral consumption of pomegranate resulted in approximately 1.5-fold increase in AUC of carbamazepine, but the IV administration of pomegranate did not cause any significant changes on AUC or t 1/2 of carbamazepine. Therefore, it was concluded that PJ component(s) impairs the function of enteric but not hepatic CYP3A [24]. Pomegranate juice was also found to inhibit the intestinal metabolism of nitrendipine without affecting its hepatic metabolism in rats [25]. Despite the large number of published in vitro and animal studiesontheeffectsofpjondrug metabolizing proteins, there are very limited clinical studies to investigate the clinical relevance of these effects in humans. Herein, we report for the first time that there are no clinically significant interactions between PJ consumption and the single dose pharmacokinetic properties of dapoxetine. The contradiction between our findings and the already published in vitro and animal studies may be attributed to the difference in concentration of pomegranate components responsible for its inhibitory effect. The most abundant phytochemicals in PJ are polyphenols, including ellagitannins, also known as punicalagins [26]. No study is currently available concerning the effects of PJ constituents on drug metabolism. Further investigations are required for identifying the possible effects of each constituent on drug metabolism. The use of midazolam in the current study enabled us to investigate the possible mechanism for this interaction. Midazolam is the most reliable standard substrate for evaluation of in vivo inhibition of CYP3A4 [27]. The increase in midazolam AUC 0?, C max and t 1/2 after GFJ indicated that the potential mechanism underlying changes in pharmacokinetics of dapoxetine by GFJ is the inhibition of intestinal and hepatic CYP3A4 enzyme. Moreover, the insignificant changes in midazolam pharmacokinetics after PJ assure the insignificant effects of PJ on CYP3A4 activity in clinical aspects. It should be noted that although midazolam and dapoxetine are CYP3A substrates, there are no reported pharmacokinetic or pharmacodynamic interactions between the two drugs either in vitro or in vivo. The pharmacokinetic parameters of both dapoxetine and midazolam in the control group (pretreatment with water) and presented in Tables 1 and 2 are similar to the published pharmacokinetic data for each drug alone, which supports the absence of any interactions between these two drugs in our study.

8 K. S. Abdlekawy et al. 6 Conclusion We show for the first time that GFJ alters the pharmacokinetic profile of dapoxetine in male healthy subjects by enhancing its exposure and reducing its clearance. The proposed mechanism is the inhibition of intestinal and hepatic CYP3A4 enzyme as indicated by the significant increase in midazolam s AUC, C max and t 1/2. Although no significant adverse effects were observed, patients should be consulted before coadminsitering dapoxetine with GFJ. In contrast, PJ appears to have minor effects on the pharmacokinetics of dapoxetine and midazolam. Thus, consumption of PJ might not be of clinical importance in the treatment with dapoxetine. Acknowledgments We thank the pharmaceutical research center in Tanta University Faculty of Pharmacy for their assistance in clinical study and HPLC analysis. We thank Dr. Marina Suzuki and Dr. Ryan Gibbard for the editorial review of the manuscript. Compliance with Ethical Standards Funding This work was supported in part by the Faculty Development Grant from Pacific University, and Research Incentive Grant from Pacific University School of Pharmacy (F. E.). Conflict of interest KSA, AMD and FE declare no conflict of interest. Ethical approval The study protocol was approved by the ethics committee of Tanta University in accordance with the Declaration of Helsinki and its amendments. Informed consent All subjects provided written informed consent before participation. References 1. Laumann EO, Paik A, Rosen RC. The epidemiology of erectile dysfunction: results from the National Health and Social Life Survey. Int J Impot Res. 1999;11(Suppl 1):S McMahon CG. Efficacy of dapoxetine in the treatment of premature ejaculation. Clin Med Insights Reprod Health. 2011;2(5): Dresser MJ, Kang D, Staehr P, Gidwani S, Guo C, Mulhall JP, et al. 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9 Modulation of Dapoxetine s Pharmacokinetics by Grapefruit and Pomegranate Juices pharmacokinetics of nitrendipine in rats. Phytother Res. 2012;26(8): Singh RP, ChidambaraMurthy KN, Jayaprakasha GK. Studies on the antioxidant activity of pomegranate (Punica granatum) peel and seed extracts using in vitro models. J Agric Food Chem. 2002;50(1): Ohno Y, Hisaka A, Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs. Clin Pharmacokinet. 2007;46(8):

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