ARS | Publication request: DO FURANOCOUMARINS MEDIATE THE GRAPEFRUIT JUICE-CYCLOSPORINE INTERACTION IN HUMANS IN VIVO?

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: April 30, 2004
Publication Date: N/A

Technical Abstract: Grapefruit juice (GFJ) can elevate blood levels of clinically important drugs, including the dual CYP3A4/P-gp substrate cyclosporine (CsA). Furanocoumarins (FCs), major mediators of the GFJ effect, inhibit intestinal CYP3A4 during absorption. However, Seville orange juice, which contains FCs in concentrations comparable to GFJ, did not interact with CsA (Edwards et al., Clin Pharmacol Ther 65:237-44, 1999), suggesting that non-FCs mediate the GFJ-CsA interaction. We therefore hypothesized that a modified GFJ, from which FCs were removed (>98%) but other major ingredients (e.g., flavonoids) retained, would still interact with CsA. This 'FC-free' GFJ was tested against orange juice (OJ) (control) and the original GFJ on the oral pharmacokinetics of CsA (5 mg/kg) in 18 healthy subjects. Blood was collected (0-24 h) and analyzed for CsA by LC/MS; each juice treatment was separated by 1 week. As expected, compared to OJ, GFJ increased the median Cmax (0.81 vs 1.05 mg/L, p=0.007), decreased the Cl/F (89 vs 64 L/h, p = 0.001), and had no effect on the terminal t½ (7.8 vs 7.5 h, p=0.3) of CsA. Unexpectedly, FC-free GFJ did not alter these measures (0.87 mg/L, 87 L/h and 7.1 h, respectively) (p 0.3). Using Caco-2 cell monolayers, compared to an ethyl acetate extract of FC-free GFJ, an extract of whole GFJ increased the AP BL (~100%) and decreased the BL AP (~50%) translocation of the P-gp probe substrate 3H-digoxin. We conclude that FCs mediate the GFJ-CsA interaction, which likely involves inhibition of transport (e.g., P-gp), in addition to CYP3A4, in the intestinal epithelium.