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Grapefruit Juice and its Constituents Augment Colchicine Intestinal Absorption: Potential Hazardous Interaction and the Role of P-Glycoprotein

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Abstract

Purpose

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 (IC50 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 (IC50 values of 90, 592 and 11.6 μM respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability.

Conclusion

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.

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  1. College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109-1065, USA

    Arik Dahan & Gordon L. Amidon

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Dahan, A., Amidon, G.L. Grapefruit Juice and its Constituents Augment Colchicine Intestinal Absorption: Potential Hazardous Interaction and the Role of P-Glycoprotein. Pharm Res 26, 883–892 (2009). https://doi.org/10.1007/s11095-008-9789-7

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