Evaluation of the effect of grapefruit juice and its components on P-glycoprotein activity

Grapefruit (Citrus paradisi Macfad.) juice (GFJ) has been demonstrated to interact with a variety of prescription medications increasing their plasma concentrations [1]. The major mechanism for GFJ-drug interaction is the inhibition of the drug-metabolizing enzyme cytochrome P-450 3A4 (CYP450 3A4) in the small intestine [2]. GFJ also interacts with intestinal P-glycoprotein (P-gp), an energy-dependent membrane efflux-transporter which restricts the absorption of a wide range of substrates [3]. However, the modulation of P-gp activity by GFJ and its clinical relevance is still unclear. The objective of this study was to compare the contents of the specific flavonoids (naringin and naringenin) and furanocoumarins (bergamottin and 6',7'-dihydroxybergamottin) in commercially available and fresh squeezed GFJ and to assess their in vitro effect on P-gp activity using Caco-2 cells and talinolol (a P-gp but a non-CYP450 3A4 substrate) as P-gp substrate. From the tested compounds the furanocoumarins 6',7'-epoxybergamottin and 6',7'-dihydroxybergamottin showed the highest inhibitory effect with IC₅₀ values of about 1µmol/L and 33µmol/L, respectively. Although not detected in any of the tested juices, naringenin showed to be three fold more potent than its glycoside naringin with IC₅₀ values of about 411 and 1250µmol/L, respectively. The in vitro data demonstrated that compounds present in grapefruit juice are able to inhibit the P-gp activity modifying the disposition of drugs that are P-gp substrates.

References: 1. Bailey, D.G. et al. (1998), Br. J. Clin. Pharmacol. 46: 101–10; 2. Schmiedlin-Ren, P. et al. (1997), Drug metab. Dispos. 25: 1228–33; 3. Spahn-Langguth, H., (2001), Eur. J. Pharm. Sci. 12: 361–367.