Effects of Lemon and Seville Orange Juices on the Pharmacokinetic Properties of Sildenafil in Healthy Subjects

Abstract

Purpose: Several severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose.

Methods: We conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration.

Results: Compared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30-60) and 18 % (90 % CI 108-129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63-75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study.

Conclusions: Although it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.

Fig. 1

Schematic of the study design

Fig. 2

Representative high-performance liquid chromatogram of a human plasma sample containing sildenafil and the internal standard propyl paraben, obtained following a single oral administration of a 50-mg sildenafil tablet. Retention times for sildenafil and propyl paraben are 6.3 and 10.2 min, respectively

Fig. 3

Mean plasma concentration of sildenafil after a single 50-mg oral administration of sildenafil with water (closed circles), or 250 mL lemon juice (open squares), or 250 mL Seville orange juice (open circles) once daily for 3 days. Mean ± standard deviation plasma concentration-time profile of sildenafil following a single 50-mg oral dose and pretreatment with water, lemon juice, or Seville orange juice once daily for 3 days

Fig. 4

Individual changes in the pharmacokinetic parameters AUC, C _max, t _1/2, and CL/F values during water, lemon juice, and Seville orange juice periods in nine healthy volunteers after oral administration of a single 50-mg dose of sildenafil. AUC area under the concentration-time curve, CL/F apparent oral clearance, C _max maximum plasma concentration, t _½ elimination half-life