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.
