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 I am from here Grapefruit comes 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:

Diastolic BP Variance Wilkinson GR N Engl J Med 2005; 352:

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 X

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,

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:

Resources for GFJ interactions Center for Food-Drug Interaction Research and Education – Maintained by the University of Florida – Provides information for consumers and HCPs –

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,

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 (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: Lilja et al Br J Clin Pharacol (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) Banfield et al Clin Pharmacokinet 41(4):