Effects of grapefruit juice on the pharmacokinetics of sildenafil.
OBJECTIVE
Because of extensive first-pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N -desmethylsildenafil, is mainly mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N -desmethylsildenafil.


METHODS
In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N -desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography-tandem mass spectrometry (limit of quantification, 1 ng/ml).


RESULTS
Grapefruit juice changed the area under the sildenafil plasma concentration-time curve from time zero to infinity [AUC(0-infinity) from 620 [1.53] ng/ml x h to 761 [1.58] ng/ml x h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%). N-Desmethyl sildenafil AUC(0-infinity) increased by 24% (90% confidence interval, 17%-32%). Maximum plasma concentrations (C(max)) of sildenafil and N -desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach C(max) during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0-0.63 hour). Interindividual variability was pronounced in both periods.


CONCLUSIONS
Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination.
Jetter
Alexander
A
Institute for Pharmacology, Clinical Pharmacology, University of Köln, Germany. alexander.jetter@medizin.uni-koeln.de
Kinzig-Schippers
Martina
M
Walchner-Bonjean
Monika
M
Hering
Ursula
U
Bulitta
Jürgen
J
Schreiner
Philipp
P
Sörgel
Fritz
F
Fuhr
Uwe
U
D000328:Adult; D019540:Area Under Curve; D001628:Beverages / Q000009:adverse effects*; D001682:Biological Availability; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D002138:Calibration; D002957:Citrus; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018565:Food-Drug Interactions / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011687:Purines; D011786:Quality Control; D000068677:Sildenafil Citrate; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D003577:Cytochrome P-450 Enzyme System; D000068677:Sildenafil Citrate; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human