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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Two Major Grapefruit Juice Components Differ in Time to Onset of Intestinal CYP3A4 Inhibition

General Clinical Research Center (M.F.P., A.B.C., P.B.W.), Division of Pharmacotherapy (M.F.P., P.B.W.), and Department of Medicine (P.B.W.), University of North Carolina, Chapel Hill, North Carolina

Grapefruit juice elevates blood levels of some drugs taken orally, primarily by inhibiting intestinal CYP3A4-mediated first-pass metabolism. Two prominent furanocoumarins in the juice, 6',7'-dihydroxybergamottin (DHB) and bergamottin (BG), have been demonstrated as important contributors to grapefruit juice-drug interactions. Using CYP3A4-expressing Caco-2 cells and representative probes from distinct CYP3A4 substrate subgroups (midazolam, testosterone), we compared the time-dependent inhibitory properties of DHB and BG. DHB rapidly inhibited CYP3A4 activity in a substrate-independent fashion with maximal inhibition (85%) generally occurring within 30 min. In contrast, BG had a slower onset and exhibited substrate-dependent inhibition. Whereas testosterone 6-hydroxylation was inhibited by >50% with all exposure times (0.5-3 h), midazolam 1'-hydroxylation was unaffected, or even activated, with short exposure times (<1 h). After a 3-h exposure, however, BG had begun to "catch up" with DHB, causing 70% inhibition, independent of substrate. Likewise, loss of CYP3A4 protein, believed to reflect rapid intracellular degradation of the enzyme following mechanism-based inactivation, was comparable between the furanocoumarins (40-50%). The time course of BG-mediated inhibition was similar after just a 30-min exposure, indicating that the short exposure presumed to occur after juice ingestion is sufficient to initiate the events required to cause substantial inhibition (50%). These results suggest that after ingestion of a glass of grapefruit juice, CYP3A4 is maximally inhibited by DHB before BG has the opportunity to act. However, foods containing BG but not DHB (e.g., lime juice) could produce a substrate-dependent interaction with drugs consumed concomitantly, but a substrate-independent interaction with drugs taken several hours after food consumption.

Address correspondence to: Dr. Mary F. Paine, General Clinical Research Center, Room 3005 Bldg. APCF, CB# 7600, UNC Hospitals, Chapel Hill, NC 27599-7600. E-mail: mpaine{at}med.unc.edu

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