Transcript Slide 1 - University of Louisiana Monroe

Grapefruit Drug Interactions:
a bitter juice to swallow
Jeffery D. Evans. PharmD
Assistant Professor of Pharmacy Practice
University of Louisiana at Monroe in
Shreveport
Objectives
• At the end of this presentation the audience
member should be able to
– Understand and apply drug – food interactions,
specifically grapefruit juice, to patient care
– Identify commonly prescribed drugs that may
have issues if taken with grapefruit juice
Full Disclosure
Grapefruit comes
from here
I am from here
The beginning
• Felodipine (Plendil) was being studied
– Concerns arose there was an interaction with
ethanol.
– Single blind trial was setup
• Placebo group got a non-alcoholic drink
• ‘Active’ got one shot of vodka
• However there was a clear difference in taste
The effect
• Both groups had
– Several fold higher concentrations of felodipine
– Significantly lower BP
– Significantly more adverse effects
• What could be causing this?
Effects of GFJ on felodipine
Systolic BP variance
Wilkinson GR N Engl J Med 2005; 352:2211 - 21
Diastolic BP Variance
Wilkinson GR N Engl J Med 2005; 352:2211 - 21
Viagra and Grapefruit juice
Viagra + GFJ
Viagra + water
Jeter A et al. Clinical Pharmacol Ther 2002 Jan; 71(1):21-9
Potential Causes for Drug-Food
Interactions
• Gut transit time
– Delayed vs accelerated gastric emptying
• Enzyme manipulation
• Transporter activity changes
Potential Mechanisms of Action
• Inactivation of Cyp 3A4
– In the gut
– In the liver
• Not just inactivation
– CYP3A4 mRNA decreases after GFJ
– Possible degradation of the enzyme
Potential Mechanisms of Action
• P-Glycoprotein (P-gp)
– A drug transporter
– Found where 3A4 is
– Excretes drugs back into the lumen
• Organic Anion Transfer Protein (OATP)
– Another drug transporter
– Not much is known, but data shows GFJ impact
Effects of GFJ on Felodipine
What is to blame for effects?
• Naringin
– A flavonoid
– Not found in other fruit juices
– In vitro data shows inhibition effects
– In vivo data does not show effects
• Quesrcetin
• Kaempferol
What is to blame for effects?
• Furanocoumarins (psoralens)
– Bergamottin
• Time dependent Cyp inactivation
• Concentration dependent Cyp inactivation
– Others found in GFJ also inactivate CYP
Duration of effect
• Separating the dose of medication and GFJ
prevents effects.
– No, not really
• First dose seems to have the same effect as
last dose of GFJ
• Effects seen as far out as seven days
So does it really matter
• Yes and Maybe
• 29 year old man
– Stable with terfenadine 60 mg BID x 1 year
– Consumed two glasses of GFJ
– Collapsed and died
– Had toxic levels of terfenadine
Spence et al Clin Pharmacol Ther 61, 395 - 400
Can they help
• Cyclosporine was a significant expense
– Undergoes 3A4 metabolism in the gut
– Transported by P-gp
– GFJ increased AUC by 60%
– Allowing for reduction in doses
Yee et al Lancet 1995; 345: 955- 956
Resources for GFJ interactions
• Center for Food-Drug Interaction Research
and Education
– Maintained by the University of Florida
– Provides information for consumers and HCPs
– http://www.druginteractioncenter.org/
Significant Interactions with GFJ
•
•
•
•
•
Amiodarone
Buspirone
Diazepam
Lovastatin
Simvastatin
Amiodarone
• Amiodarone with GFJ increased
– AUC by 50%
– Maximum concentration by 84%
• Trial
– Single dose
– Healthy adults
– Significant amount of GFJ
Libersa CC et al J Clin Pharmacol. 49, 373 - 379
Buspirone
• Buspirone when taken with GFJ
– AUC increased 9 fold
– Peak concentration increased 4.3 fold
– Time to peak concentration was delayed from
0.75 hours to 3 hours
• Trial
– Run in phase of three days
– Double strength GFJ used
Lilja et al Clin Pharmacol Ther 1998;64:655-60
Buspirone
Lilja et al Clin Pharmacol Ther 1998;64:655-60
Diazepam
• Use of diazepam and GFJ increased
– AUC 3.2 fold
– Maximum concentration 1.5 fold
• Trial facts
– Small student
– Unknown quantities of GFJ
– Single dose
Ozdemir M et al Eur J Drug Metab Pharmacokinet 1998 23(1):55-9
Lovastatin
• Use of lovastatin and GFJ
– With 2x strength
• 12 fold increase in peak concentration
• 15 fold increase in AUC
– With 1x strength
• 1.3 fold increase in peak concentration
• 1.3 fold increase in AUC
Kantola et al Clin Pharmacol Ther 1998; 63:397 – 402
Rogers et al Clin Pharmacol Ther 1999;66:358-66
Simvastatin
• Use of simvastatin and GFJ
– With 2x strength GFJ
• 12 fold increase in peak serum concentration
• 13.5 fold increase in AUC
– With 1x strength
• 3.9 fold increase in peak serum concentration
• 3.6 fold increase in AUC
Lilja et al Clin Pharmacol Ther 2000; 68:384-90
Lilja et al Br J Clin Pharacol 2004 58(1):56- 60
Parting thoughts
• Drugs to be probably concerned about
– Atorvastatin 1.4 AUC increase, 1.6 Conc increase
– Fexofenadine 30% reduction in bioavailability
Fukazawa et al Br J Clin Pharmacol 57(4) 448-455
Banfield et al Clin Pharmacokinet 41(4):311- 318