Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin

Abstract

AimsSimvastatin, a substrate for CYP3A4, is extensively metabolized during the first pass. Our aim was to investigate the effect of regular consumption of g rapefruit juice on the pharmacokinetics of simvastatin. MethodsIn a randomized cross-over study with two phases, 10 healthy volunteers ingested grapefruit juice 200 ml or water (control) for 3 days. On day 3, a single 40-mg dose of simvastatin was administered with grapefruit juice 200 ml or water. Plasma concentrations of simvastatin and simvastatin acid were determined up to 24 h. ResultsGrapefruit juice increased the area under the plasma concentration-time curves from 0 to 24 h [AUC(0-24)] of simvastatin 3.6-fold (range 1.8-6.0-fold; P < 0.01) and that of simvastatin acid 3.3-fold (range 2.1-5.6-fold; P < 0.01), respectively. The peak concentrations ( C max ) of simvastatin and simvastatin acid were increased 3.9-fold (range 2.3-9.3-fold; P < 0.01) and 4.3-fold (range 2.7-7.9-fold; P < 0.01) by grapefruit juice. ConclusionsEven one glass of grapefruit juice, taken daily, considerably increases the plasma concentrations of simvastatin and simvastatin acid. Grapefruit juice may increase both the cholesterol-lowering effect and the risk of adverse effects of simvastatin.

Absorption and pharmacokinetics of grapefruit flavanones in beagles

“…Several studies have shown that grapefruit juice elevates the blood levels of some orally taken drugs, primarily by inhibiting intestinal CYP3A4-mediated first-pass metabolism (Fuhr et al 2002;Dahan & Altman, 2004;Lilja et al 2004;Paine et al 2004Paine et al , 2005, CYP3A4 being a type of cytochrome P450. These studies suggest a potential therapeutic benefit from using the active constituents of grapefruit to increase drug bioavailability.…”

Essentials of Herb-Drug Interactions in the Elderly With Cardiovascular Disease

“…This effect is present whether grapefruit is taken as a whole fruit or in juice form, causing clinically relevant increase in blood concentration of affected drugs that can result in adverse effects. 170 Some examples include exaggerated antihypertensive response with calcium channel blockers (felodipine), 171 increased risk of rhabdomyolysis and hepatotoxicity with statins, 168 hypoglycemia with antidiabetics (repaglinide), increased steady-state concentration of cyclosporine, potentiation of toxicity with antiarrhythmics with QT prolongation and torsades de pointes, 172 and augmentation of antiplatelet activity of cilostazol leading to pupura. 173 There also are case reports of elevated INR and hematoma with grapefruit juice ingestion in patients previously stabilized on warfarin.…”

“…Even a single exposure to one glass of the grapefruit juice can produce clinically significant interaction, and with the half-life of CYP3A4 being > 8 hours, its reversal inhibition by grapefruit increases the bioavailability and blood levels of drugs metabolized by this enzyme (Table 3) up to 72 hours. 168,169 Therefore, repeated juice intake can result in adverse effects even if not taken concomitantly with drugs. This effect is present whether grapefruit is taken as a whole fruit or in juice form, causing clinically relevant increase in blood concentration of affected drugs that can result in adverse effects.…”

In Vivo and in Vitro Study on Drug-Drug Interaction of Lovastatin and Berberine from Pharmacokinetic and HepG2 Cell Metabolism Studies

“…The literature has reported drug-drug interactions between lovastatin and drugs or related products with effect on drugs such as colesevelam, gemfibrozil, itraconazole or dietary supplements determined via pharmacokinetic studies [10][11][12][13][14][15]. Berberine is an alkaloid available from the medicinal plant Coptis chinensis that is widely used clinically in the treatment of gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia.…”

“…In the in vitro HepG2 cells experiments, berberine could increase the metabolic activity by increasing the metabolic parameters of CL, which was increased from 1.06 to 1.48 mL/10 5 (cell)·h −1 with the induction of berberine, the Km was increased three times in berberine induced group as well, which was compliance with the obtained pharmacokinetics parameter from AUC0-12 of lovastatin decreased 2.5 times (approximately three times). The literature has reported drug-drug interactions between lovastatin and drugs or related products with effect on drugs such as colesevelam, gemfibrozil, itraconazole or dietary supplements determined via pharmacokinetic studies [10][11][12][13][14][15]. Berberine is an alkaloid available from the medicinal plant Coptis chinensis that is widely used clinically in the treatment of gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia.…”