Exploring mechanisms of grapefruit juice drug interactions and its potential toxicity

Abstract

Grapefruit juice (GFJ) inhibits not only the drug-metabolizing enzyme cytochrome P-450 3A4 (CYP3A4) in the small intestine [1], but also interacts with intestinal P-glycoprotein (P-gp), a membrane efflux-transporter [2]. Using a Caco-2 cell culture model we determined the permeability of talinolol across monolayer membranes in absence and presence of GFJ and several of its components. 6',7'-epoxybergamottin was the most potent inhibitor (IC50=0.7µM), followed by 6',7'-dihydroxybergamottin (IC50=34µM). Naringenin was around 10-fold more potent than its glycoside naringin with IC50 values of 207 and 2814µM, respectively. Whereas the effect of a single dose of GFJ on the pharmacokinetics of several drugs has been studied extensively [3], data concerning the effect of grapefruit juice on the pharmacokinetics of CYP3A4 substrates after repeated use are limited. We investigated the interaction between GFJ and simvastatin in a time and dose dependent manner in rats. When simvastatin was administered alone in a concentration of 200mg/kg (p.o.), the 50% survival rate after 10 days limited the further duration of the experiment. When simvastatin (20mg/kg, p.o.) and GFJ (5ml/kg) were given concomitantly for 4 consecutive weeks, no signs of toxicity were observed. Although it has been shown that consumption of a single glass of GFJ (200ml) can increase the serum levels of the parent drug simvastatin up to 16fold [4], it is possible that this pharmacokinetic interaction does not necessarily have to result in a pharmacodynamic interaction and may occur only under single dose conditions.