PMID- 22940371 OWN - NLM STAT- MEDLINE DCOM- 20130322 LR - 20131121 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 34 IP - 10 DP - 2012 Oct TI - Effects of grapefruit and Seville orange juices on the pharmacokinetic properties of colchicine in healthy subjects. PG - 2161-73 LID - S0149-2918(12)00488-2 [pii] LID - 10.1016/j.clinthera.2012.08.007 [doi] AB - BACKGROUND: The labeling for colchicine (indicated for acute gout flares or prophylaxis) includes strict advisories regarding drug-drug and drug-food interactions, including warnings against consuming grapefruit or grapefruit juice during treatment. Two of the furocoumarins in grapefruit juice and Seville orange juice can inhibit intestinal cytochrome P450 (CYP) isozyme 3A4 and P-glycoprotein (involved in colchicine metabolism and transport). Severe toxicities in patients consuming these juices while taking other drugs metabolized through these pathways have been reported. OBJECTIVE: Two Phase I studies assessed the effects of multiple daily consumptions of Seville orange juice or grapefruit juice on the pharmacokinetic properties of colchicine in healthy volunteers. METHODS: Healthy volunteers were enrolled in 2 open-label, Phase I studies. Undiluted juice (240 mL) was administered twice daily for 4 days. Pharmacokinetic data were obtained following a single 0.6-mg dose of colchicine before the administration of juice and again following a single 0.6-mg dose of colchicine on the final day of juice administration. In each study, blood samples for pharmacokinetics were collected before dosing with colchicine and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose. All subjects were monitored for adverse events (AEs) throughout the confinement portion of the study and were queried at the outpatient visits. AEs were coded according to corresponding MedDRA-coded system organ classes. RESULTS: Forty-four subjects received either grapefruit juice (72.7% male; 90.9% white) or Seville orange juice (62.5% female; 100% white). Although it is considered to be a moderate concentration-dependent CYP3A4 inhibitor, grapefruit juice did not significantly affect the pharmacokinetic parameters of colchicine. When colchicine was administered with Seville orange juice, a moderate inhibitor, C(max) and AUC were decreased by approximately 24% and approximately 20%, respectively. Seville orange juice also caused, on average, a 1-hour delay in T(max). Colchicine in combination with grapefruit or Seville orange juice was well tolerated. There were no significant treatment-related AEs reported, and the most likely AEs were general gastrointestinal events. CONCLUSIONS: In contrast to label warnings based on the literature, grapefruit juice did not affect the pharmacokinetics of colchicine. Seville orange juice paradoxically reduced absorption of colchicine and increased T(max), but the clinical significance of this is unknown. Contrary to the expected effects of inhibiting the enzymes that metabolize colchicine, neither juice increased exposure to colchicine. However, the absence of a positive control in these studies dictates that caution should be used when applying these results clinically. ClinicalTrials.gov identifiers: NCT00960193 and NCT00984009. CI - Copyright (c) 2012 Elsevier HS Journals, Inc. All rights reserved. FAU - Wason, Suman AU - Wason S AD - URL Pharma, Inc, Philadelphia, Pennsylvania, USA. swason@urlpharma.com FAU - DiGiacinto, Jennifer L AU - DiGiacinto JL FAU - Davis, Matthew W AU - Davis MW LA - eng SI - ClinicalTrials.gov/NCT00960193 SI - ClinicalTrials.gov/NCT00984009 PT - Clinical Trial, Phase I PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120831 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Gout Suppressants) RN - SML2Y3J35T (Colchicine) SB - IM MH - Adolescent MH - Adult MH - Beverages MH - Citrus/*chemistry MH - Citrus paradisi/*chemistry MH - Colchicine/adverse effects/*pharmacokinetics MH - Drug Labeling MH - Female MH - *Food-Drug Interactions MH - Gout Suppressants/adverse effects/pharmacokinetics MH - Humans MH - Male MH - Middle Aged MH - Time Factors MH - Young Adult EDAT- 2012/09/04 06:00 MHDA- 2013/03/23 06:00 CRDT- 2012/09/04 06:00 PHST- 2012/05/30 00:00 [received] PHST- 2012/08/14 00:00 [revised] PHST- 2012/08/16 00:00 [accepted] PHST- 2012/09/04 06:00 [entrez] PHST- 2012/09/04 06:00 [pubmed] PHST- 2013/03/23 06:00 [medline] AID - S0149-2918(12)00488-2 [pii] AID - 10.1016/j.clinthera.2012.08.007 [doi] PST - ppublish SO - Clin Ther. 2012 Oct;34(10):2161-73. doi: 10.1016/j.clinthera.2012.08.007. Epub 2012 Aug 31.