Grapefruit juice and its constituents augment colchicine intestinal absorption: potential hazardous interaction and the role of p-glycoprotein.
OBJECTIVE
To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate.


METHODS
Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP-BL and BL-AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6'-7'-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined. The effect of GFJ on colchicine intestinal-permeability was then investigated in-situ in the rat perfusion model, in both jejunum and ileum.


RESULTS
Colchicine exhibited 20-fold higher BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion, which was reduced by verapamil/quinidine. Colchicine AP-BL permeability was increased and BL-AP was decreased by GFJ in a concentration-dependent manner (IC(50) values of 0.75% and 0.46% respectively), suggesting inhibition of efflux transport, rather than metabolizing enzyme. Similar effects obtained following pre-experiment incubation with GFJ, even though the juice was not present throughout the transepithelial study. 6'-7'-Dihydroxybergamottin, naringin and naringenin displayed concentration-dependent inhibition on colchicine BL-AP secretion (IC(50) values of 90, 592 and 11.6 microM respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability.


CONCLUSIONS
The data suggest that GFJ may augment colchicine oral bioavailability. Due to colchicine narrow therapeutic-index and severely toxic side-effects, awareness of this interaction is prudent.
Dahan
Arik
A
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109-1065, USA.
Amidon
Gordon L
GL
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001628:Beverages / Q000009:adverse effects*; D018938:Caco-2 Cells; D016764:Cell Polarity; D032083:Citrus paradisi / Q000737:chemistry; D003078:Colchicine / Q000008:administration & dosage / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D044950:Flavanones / Q000302:isolation & purification / Q000494:pharmacology; D018565:Food-Drug Interactions; D005638:Fruit; D011564:Furocoumarins / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010539:Permeability; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018570:Risk Assessment; D013997:Time Factors; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044950:Flavanones; D011564:Furocoumarins; D050257:Tubulin Modulators; D014700:Verapamil; C005273:naringenin; D011802:Quinidine; C005274:naringin; C104774:6',7'-dihydroxybergamottin; D003078:Colchicine