The part of furocoumarins in grapefruit juice .

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The role of furocoumarins in grapefruit juice/drug interactions. . Paul B. Watkins University of North Carolina Chapel Hill, N.C. “Grapefruit Effect On Drug Levels Has Sweeter Side” By SYLVIA PAGÁN WESTPHAL November 27, 2007; Page D1 Wall Street Journal.
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The part of furocoumarins in grapefruit juice/medicate collaborations. Paul B. Watkins University of North Carolina Chapel Hill, N.C.

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"Grapefruit Effect On Drug Levels Has Sweeter Side" By SYLVIA PAGÁN WESTPHAL November 27, 2007; Page D1 Wall Street Journal

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King\'s specialist recommended Lipitor, alongside proceeded with eating routine and work out. Ruler complied. His Lipitor dosage was bit by bit expanded to a high measurements of 60 milligrams a day. Following four months, he\'d brought his LDL cholesterol down to 104. He\'d additionally lost 36 pounds. Later, King made a beeline for his winter home in Florida. With a grapefruit tree on his porch, he drank a few day by day glasses of new grapefruit juice. Yet, only two months subsequent to getting the uplifting news about his cholesterol, King was in a Florida crisis room. His manifestations: muscle torment that had begun all of a sudden, weakness, and high fever. Ruler was determined to have rhabdomyolysis, a serious muscle response that can bring about death. Web MD - 2005

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[drug] time Interpatient variety in pharmacokinetics

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First Pass Metabolism

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First Pass Metabolism

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LOCATION OF INTESTINAL CYP3A4 Kolars et al. (1994) Pharmacogenetics 4:247-59

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[drug] time Effect of Grapefruit squeeze on serum levels of an a few medications

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Some medications affected by grapefruit juice Drug AUC increment felodipine ~ 3 overlay cisapride ~ 1.4 fold cyclosporine ~ 1.5 overlap saquinavir ~ 2 crease terfenadine ~ 2.5 overlap buspirone ~ 9 crease lovastatin/simvastatin ~ 10 crease

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8/30/02 email "… .. our business viewpoint has been extraordinarily tested by the grapefruit - sedate cooperation and the way it is being conveyed (frequently incorrectly) to the general population… Jay Dravenstadt Manager R&D, Grapefruit Business Ocean Spray Cranberries Lakeville-Middleboro, MA 02349

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Hypothesis Grapefruit juice communications are not clinically imperative on the grounds that intestinal CYP3A4 is upregulated (prompted) in individuals who routinely drink the juice.

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Clinical Study 10 solid grown-ups were admitted to the GCRC and got one glass of grapefruit juice (8 oz) with every dinner for 7 days Endoscopy with "squeeze biopsies" performed prior and then afterward. Biopsy substance of CYP3A4 protein and mRNA measured

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GFJ REDUCES INTESTINAL CYP3A4 PROTEIN GFJ lessened CYP3A4 protein content in all subjects Lown et al. (1997) JCI 99:2545-53

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Conclusions Hypothesis is totally off-base. GFJ makes CYP3A4 leave!

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Screening HLPC parts (Fraction C) for capacity to repress CYP3A4 in human intestinal microsomes

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Furocoumarins in Grapefruit Juice O H O H O 6,7-dihydroxybergamottin (DHB) Bergamottin O H O H O H O FC708 FC726

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Caco-2 Cells Derived from a human colon adenocarcinoma Upon separation take after little intestinal enterocytes within the sight of 1 a ,25-(OH) 2 - D 3 express CYP3A4 Schmiedlin-Ren et al. Mol Pharmacol 51: 741-754, 1997 Basolateral medium embed apical medium culture dish Caco-2 cell monolayer

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Time course of the impact of DHB on CYP3A4 2 hr 2 hr 4 hr 3 hr 4 hr 8 hr 0 hr 1 hr 1 hr 3 hr 8 hr 12 hr 12 hr 0.5 hr 0.5 hr 3A4 Standards DHB Vehicle Unpublished information

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Is this lessening in CYP3A4 protein content because of diminished rate of amalgamation or quickened rate of debasement?

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Pulse 35 S 2 hours (methionine Free) 35 S-Methionine 35 S Chase 35 S Medium with 6X icy Methionine 0-48 hours Degradation 35 S Pulse Chase Culture Medium Protein Synthesis

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Vehicle k deg = 0.048h - 1 t 1/2 = 14.4h DHB k deg = 0.21h - 1 t 1/2 = 3.1h 4 12 0.5 8 1 2 Effect of DHB on the Degradation of CYP3A4 (Pulse Chase 35 S named Met/Cys) CYP3A4 0 4 12 24 48 0.5 8 1 2 DHB Vehicle Unpublished information

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Ub Ubiquitination X Lactocystin Peptides Ubiquitin-Proteasome Pathway DDEP P450 Inactivation DDEP Proteasome

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Physiologic DDEP inactivated DHB inactivated Ub Ubiquitinating Enzymes Ub CYP3A4 Inactivation Ubiquitination Peptides Summary Proteasome

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Summary DHB quickens the rate of CYP3A4 debasement while having no impact on the rate of its amalgamation This outcomes in a fall in CYP3A4 half life from 14h to 3 h.

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Modeling single organization GFJ impact for measurement and time course Takanaga, et al, Br. J. Clin Pharmacol. 49,49,2000.

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FEL gut lumen enterocyte into the body

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FEL * CYP3A4 Gut lumen enterocyte Into the body

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FEL FC FC* FC CYP3A4 Gut lumen enterocyte X Into the body

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FEL FC FC* FC Gut lumen enterocyte Into the body

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Where is this examination headed? 1). Advancement of new apparatuses for human research 2). Enhancements in oral medication conveyance 3). New grapefruit juice

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Saquinavir 1). Most broadly utilized HIV protease inhibitor 2). Oral accessibility 4-14% 3). Exceptionally fast digestion system by CYP3A4

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Effect of SOJ on AUC of Saquinavir JPET 308:941-948, 2004

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Where is this exploration headed? 1). Improvement of new instruments for human research 2). Changes oral medication conveyance 3). New grapefruit juice

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Range of variety in enterocyte CYP3A4 content in grown-ups 10 0

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Variation in enterocyte CYP3A4 action and the oral mien of a few substrates 10 0

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Conclusion Grapefruit juice/tranquilize associations are of negligible significance in light of the fact that emotional increments in oral accessibility just happen in those patients who have low oral accessibility at benchmark

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Effect of GFJ on Cisapride Gross et al, CPT 65:395,1999

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"In Florida, Bioavailability Systems LLC, a little biotechnology organization, cases to have cleaned the grapefruit mixes in charge of the boosting impact and has possessed the capacity to enhance the blood levels of an against HIV sedate. "This is certainly a lemons to lemonade story," says James Harris , author and boss logical officer of the organization. " November 27, 2007; Page D1 Wall Street Journal

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Reasons why grapefruit juice/medicate connections shouldn\'t be essential: 1). Powerless medications must have incredible safety profile in spite of vast interpatient variation in presentation. 2). Individuals with low intestinal CYP3A4 activity will be experienced in clinical trials.

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Situations where grapefruit juice/medicate associations may once in a while turn out to be clinically huge: 1). Patient is requiring higher than common dosage of "susceptible" medication and starts drinking juice surprisingly. 2). Understanding has extreme liver infection. 3). Tolerant has an exceptional helplessness to a adverse impact.

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Where is this examination headed? 1). Advancement of new instruments for human research 2). Upgrades oral medication conveyance 3). New grapefruit juice

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Elimination of Furanocoumarins from GFJ Retentate Juice Ultrafilration Ethyl Acetate Serum Pectin + Cellulose Furanocoumarins + Flavonoids Debitter Debittered Serum Absorbed Conc. + EtOH + Flash Chromatography Etute + EtOH +Flash Chromatography Flavonoids FC 6,7-DHB Flavonoids Clinical Test Juice Commercial FCF Flavor Package

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Felodipine study plan 18 subjects conveyed to GCRC Three-way randomized hybrid outline. 10 mg maintained discharge tablet of felodipine (Plendil) given with OJ, GFJ, or sans fc GFJ. Blood tests (10-mL) gathered at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours.

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Felodipine association think about Felodipine (nM) Time (hours) n = 18 Am. J. of Clin. Nutr. 83(5):1097-105, 2006

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Conclusion 1). It is conceivable to expel significant FCs from grapefruit juice. 2). This may not evacuate all GFJ/sedate cooperations.

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Fexo CsA Pgp OATP CYP3A4 gut lumen enterocyte into the body

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" One such compound called naringin influences the viability of the prevalent hypersensitivity medicate Allegra by hindering these transporters. "Even an ordinary glass of juice will lessen the impacts of Allegra by half," says Dr. Bailey, whose group made the revelation a year ago. "It\'s the tip of the iceberg," he includes. "Big pharma is exceptionally interested." " November 27, 2007; Page D1 Wall Street Journal

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Thanks Florida Dept of Citrus Bill Widmer, Ph.D. Charge Stinson,Ph.D. Mary Paine, PhD. Shefali Malhotra Anne Criss Susan Pusek Stephane Mouly National Institutes of Health General Medical Sciences R37-38149 General Clinical Research Centers (NCRR).

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