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

Abstract

PurposeSeveral 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.MethodsWe 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.ResultsCompared 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.ConclusionsAlthough 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.

Screening of furanocoumarin derivatives as cytochrome P450 3A4 inhibitors in citrus

“…However, Abdelkawy et al. reported that lemon does not affect the pharmacokinetics of sildenafil . Based on this information, it was likely that the citrus fruits investigated in this study that contained more DHB than pummelo would induce drug interactions mediated by the inhibition of CYP3A4 and that citrus fruits that contained less DHB than lemon would be safe.…”

Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p‐Synephrine

“…The primary active ingredients in Citrus responsible for these effects are the furanocoumarins bergapten, bergamottin, and 6′,7′‐dihydroxybergamottin (Guo et al ., ; Paine et al ., ; Fujita et al ., ; Messer et al ., ; Greenblatt et al ., ). Studies have shown that Seville, mandarin, and clementine orange juices have the potential to produce drug interactions (see, for example, Abdelkawy et al ., ; Theile et al ., ), presumably due to their furanocoumarin content. Gurley et al .…”

“…The primary active ingredients in Citrus responsible for these effects are the furanocoumarins bergapten, bergamottin, and 6 0 ,7 0 -dihydroxybergamottin (Guo et al, 2000;Paine et al, 2006;Fujita et al, 2008;Messer et al, 2011;Greenblatt et al, 2012). Studies have shown that Seville, mandarin, and clementine orange juices have the potential to produce drug interactions (see, for example, Abdelkawy et al, 2016;Theile et al, 2016), presumably due to their furanocoumarin content. Gurley et al (2004) showed that, in humans receiving 30.6 mg of p-synephrine per day in the form of a bitter orange (C. aurantium), no significant effects were observed on CYP3A4, CYP1A2, CYP2D6, or CYP2E1, the major drug-metabolizing cytochrome enzymes.…”

Therapeutic Implications of a Polymethoxylated Flavone, Tangeretin, in the Management of Cancer via Modulation of Different Molecular Pathways

“…Tangeretin is present in the bitter orange peel of Seville orange, the Seville juice was reported to inhibit intestinal cytochrome P450 (CYP) isozyme 3A4, and P-glycoprotein was shown to affect colchicine metabolism and transport, which can lead to severe toxicity [ 76 ]. Sildenafil bioavailability is reported to be improved by Seville orange; this can be contributed to the inhibition of its intestinal first-pass effect of CYP3A4 and/or P-gp [ 77 ]. On the other hand, tangeretin was reported as a potent regioselective stimulator causing CYP3A4 induction [ 73 , 78 ].…”