Effects of Grapefruit and Pomegranate Juices on the Pharmacokinetic Properties of Dapoxetine and Midazolam in Healthy Subjects.
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 (AUC0-∞) and peak plasma concentration (Cmax) of dapoxetine by 60 and 80 %, respectively, and prolonged its elimination half-life (t1/2) by 43 %. Similar effects of GFJ on the pharmacokinetics of midazolam were observed with a significant increase in AUC0-∞(75 %), Cmax(40 %), and t1/2(92 %). Slight but not statistically significant changes were observed in the pharmacokinetics of dapoxetine and midazolam after pretreatment with PJ. Time to reach Cmax(Tmax) did not differ among the three phases.


CONCLUSIONS
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.
Faculty of Pharmacy, Kafrelsheikh University, Kafr el-Sheikh, Egypt.
Khaled S
KS
Abdlekawy
Faculty of Pharmacy, Tanta University, Tanta, Egypt.
Ahmed M
AM
Donia
School of Pharmacy, Pacific University, 222 SE 8th Ave., Hillsboro, OR, 97123, USA. Fawzy.elbarbry@pacificu.edu.
Fawzy
F
Elbarbry
D000328:Adult; D019540:Area Under Curve; D001596:Benzylamines / Q000493:pharmacokinetics*; D001628:Beverages / Q000009:adverse effects*; D032083:Citrus paradisi / Q000009:adverse effects*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D018565:Food-Drug Interactions / Q000502:physiology*; D000067030:Fruit and Vegetable Juices / Q000009:adverse effects*; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D029561:Lythraceae / Q000009:adverse effects*; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D009281:Naphthalenes / Q000493:pharmacokinetics*
D001596:Benzylamines; D009281:Naphthalenes; D051544:Cytochrome P-450 CYP3A; C080598:dapoxetine; D008874:Midazolam