Effects of grapefruit juice on the pharmacokinetics of sildenafil.

摘要: Background And Objectives Because of extensive first-pass metabolism, oral bioavailability sildenafil reaches only 40%. Formation the primary metabolite, N-desmethylsildenafil, is mainly mediated by cytochrome P450 enzyme CYP3A4. In this study we investigated influence grapefruit juice, containing inhibitors intestinal CYP3A4, on pharmacokinetics and N-desmethylsildenafil. Methods In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses sildenafil. Two each 250 ml juice or water, respectively, were administered 1 hour before together with drug. Plasma concentrations N-desmethylsildenafil determined up to hours post dose use liquid chromatography–tandem mass spectrometry (limit quantification, ng/ml). Results Grapefruit changed area under plasma concentration–time curve from time zero infinity [AUC(0-∞)] 620 [1.53] ng/ml • h 761 [1.58] (geometric mean geometric standard deviation), corresponding 23% increase (90% confidence interval, 13%-33%). N-Desmethylsildenafil AUC(0-∞) increased 24% 17%-32%). Maximum (Cmax) essentially unchanged. There was trend toward prolonged reach Cmax during period (from median 0.75 1.13 hours), an 0.25 0–0.63 hour). Interindividual variability pronounced in both periods. Conclusions Grapefruit increases tends delay absorption. Sildenafil may become less predictable juice. Although patients usually will not be endangered concomitant it seems advisable avoid combination. Clinical Pharmacology & Therapeutics (2002) 71, 21–29; doi: 10.1067/mcp.2002.121236