kayla jester april 18, 2011 micronutrient metabolism

THE EFFECTS OF GRAPEFRUIT JUICE ON THE METABOLISM OF

STATIN MEDICATIONS

Kayla JesterApril 18, 2011Micronutrient Metabolism

Outline

Research Question Methodology Overview of:

Drug-drug and drug-food interactions Statin drugs Components of grapefruit juice

Research Results Discussion/Conclussion Recommendations and applications to

practice

Introduction

Research Question: Which statin medications have an

interaction with grapefruit juice, and are there alternate options for individuals who are prescribed statins but still desire to consume grapefruit juice?

Why are statin drugs important?

Importance of Drug Interactions and Statins Centers for Disease Control and

Prevention reported: 700,000 visits to the emergency rooms

and more than 120,000 hospitalizations a year were due to adverse drug reactions

The leading cause of death in the United States in 2007 was cardiovascular disease High cholesterol is a contributing factor to

CVD Can assume a large number of people are on

statin medications1. Centers for Disease Control ad Prevention. http://www.cdc.gov/MedicationSafety/basics.html. Updated September 24, 2010. Accessed April 5, 2011.

Methodology

Background –Statin Drugs

Use of statins: Prescribed to

decrease blood cholesterol levels

Statin drugs prevent the biosynthesis of cholesterol by inhibiting HMG-CoA reductase, the enzyme responsible for the conversion of HMG-CoA to mevalonate.

1. Fukazawa I, Uchida N, Uchida E, Yasuhara H. Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese. Br J Clin Pharmacol. 2004; 57(4): 448-455.

2. Statins Inhibit Growth of Human Endometrial Stromal Cells Independently of Cholesterol Availability. http://www.biolreprod.org/content/75/1/107/F5.expansion. Accessed April 10, 2010.

Statins

The metabolic route of the statin medications in the body is dependent on the specific synthetic form of statin taken. Failure to metabolize and excrete statin drugs could lead to

potential side effects including: Myopathy Rhabdomyolosis

There are currently seven forms of statin drugs on the market:

Rosuvastatin (Crestor®)Atorvastatin (Lipitor®)Simvastatin (Zocor®)Pravastatin (Pravachol®)

Fluvastatin (Lescol®)Lovastatin (Mevacor®)Pitavastatin (Livalo®)

4. Moll J. Can I take statins and grapefruit together. Available at: http://cholesterol.about.com/od/statindrugs/algrapefruitstat.htm. Accessed February 4, 2011.

5. Kajinami K, Takekoshi N, Saito Y. Pitavastatin: Efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. Cardiovascular Drug Reviews. 2003; 21(3): 199-215.

6. HIV Web Study. Drug-Drug Interactions. http://depts.washington.edu/hivaids/drug/case5/discussion.html. Accessed April 9, 2011

Background –grapefruit juice

There are high amounts of vitamins C as well as citric acid, essentail oils, phytonutrients, and other nutrients that benefit health in grapefruit and grapefruit juice

Important components thought to cause an interaction with statin medications include furanocoumarins bergamottin and 6’7’-dihydroxybergamottin, and flavonoids naringin and naringenin7. Ho P, Saville D. Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds. J Pharm Pharmaceut Sci. 2001; 4(3): 217-227.

Research- M. Paine et al. The components responsible for CYP3A4

inhibition in grapefruit juice Location: University of North Carolina Randomized, 3-way crossover study

18 volunteers (9 men/9 women) GFJ, OJ, or FC-free GFJ was consumed with felodipine This study found there was a significant increase in

the AUC and Cmax of felodipine with simultaneous consumption of GFJ No effects observed with joint consumption of OJ or FC-

free GFJ

What can be concluded: Furanocoumarins are the components in GFJ

responsible for the inhibition of CYP3A4

8. Paine M, Widmer W, Hart H, Pusek S, Beavers K, Criss A, Brown S, Thomas B, Watkins P. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice–felodipine interaction.

Research

Graph A: The plasma concentration-time profile for the smallest GFJ-mediated increase in a subject

Graph B: The plasma concentration-time profile for the largest GFJ-mediated increase in a subject

Graph C: Representation of the median plasma concentration-time profile for all 18 subjects

8. Paine M, Widmer W, Hart H, Pusek S, Beavers K, Criss A, Brown S, Thomas B, Watkins P. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice–felodipine interaction

Research- J. Lilja et al. Effects of GFJ on simvastatin

Location: University of Helsinki, Finland Randomized, 2-phase crossover study

10 subjects Received 200 mL GFJ or water for two days, and on the

third day took a 40 mg dose of simvastatin with GFJ or water Studies repeated and subjects served as their own controls

This study found that the AUC and Cmax of simvastatin increased with joint utilization of GFJ

What can be concluded: Increased plasma concentration levels show that

simvastatin is one synthetic form of statin drug affected by GFJ consumption Metabolized by CYP3A4

9. Lilja J, Neuvonen M, Neuovonen P. Effects of regular consumption of grapefruit juice on the pharmacokinetis of simvastatin. Br J Clin Pharmacol. 2004; 58(1): 56-60.

Research- I. Fukazawa et al. Comparison of Atorvastatin and Pravastatin plasma

concentrations with GFJ consumption Location: Tokyo, Japan 2 Randomized, 2-way crossover studies

20 total participants, split into two groups of 10 Study I: Given 250 mL of GFJ for two days and on third day took

___ mg pravastatin along with GFJ Trial was repeated with water

Study II: Given 250 mL of GFJ for two days and on third day took ___ mg atorvastatin along with GFJ Trial was also repeated with water

Found an increase in the AUC and Cmax of atorvastatin when taken with GFJ, but no change in pravastatin plasma concentraitons

What can be concluded: Atorvastatin is metabolized by CYP3A4, while pravastatin has a

different metabolic patheway10. Fukazawa I, Uchida N, Uchida E, Yasuhara H. Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in

Japanese. Br J Clin Pharmacol. 2004; 57(4): 448-455.

Research- H. Ando et al. Comparison of Atorvastatin and Pitavastatin

plasma concentrations with GFJ consumption Location: Tochigi, Japan Randomized, 4-phase crossover study

8 subjects Randomly administered 250 mL GFJ or water for 3

consecutive days and on each study day received 4 mg pitavastatin or 20 mg atovastatin

The study found an increase in the AUC and Cmax of atorvastatin in the plasma with GFJ consumption, but no significant difference was found with pitavastatin

What can be concluded: Atorvastatin is metabolized by CYP3A4, while

pitavastatin has a different metabolic patheway

Example Phase 1 Phase 2Phase 3 Phase 4

Participant GFJ + GFJ+ Water+Water +

Pitavastatin Atorvastatin PitavastatinAtorvastatin

11. Ando H, Tsuruoka S, Yanagihara H, Sugimoto K, Miyata M, Yamazoe Y, Takamura T, Kaneko S, Fujimura A. Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin. Br J Clin Pharmacol. 2005; 60(5): 494-497.

Discussion/Conclusion

Strengths Most studies were statistical significant

(P<0.05) Subjects served as their own controls

Limitations Small sample size Little exclusion criteria

Could other factors cause inaccurate findings?

Only 1 of 3 studies analyzed furanocoumarin concentrations in GFJ

Discussion/Conclusion

What are the components in grapefruit juice responsible for inhibition of CYP3A4? M. Paine furanocoumarins Other studies Flavanoids and furanocoumarins

Different results between studies could be a result of: Different dose amounts of statins given Ethnicity Different inherent ability to metabolize statins

No dietetic involvement mentioned Statins metabolized by the cytochome P450-3A4

should not be consumed with GFJ due to its inhibitory effects on the isoenzymes of the complex

Recommendations/ Applications to Practice All healthcare providers should make

sure an individual knows not to consume grapefruit juice if on statin medications metabolized by CYP3A4

Provide alternative options Orange juice Statin drug not metabolized by CYP3A4 Abstain from statin use

Healthy life-style

Applications to Practice

Dietitians Should become more involved in statin-GFJ

studies, as well as other drug-food interaction studies

Provide advice on how to avoid statin use Losing weight More physically active Healthier diet

High in soluble fiber and monounsaturated fats Low in saturated fats and cholesterol

References

1. Centers for Disease Control ad Prevention. http://www.cdc.gov/MedicationSafety/basics.html. Updated September 24, 2010. Accessed April 5, 2011.


3. Statins Inhibit Growth of Human Endometrial Stromal Cells Independently of Cholesterol Availability. http://www.biolreprod.org/content/75/1/107/F5.expansion. Accessed April 10, 2010.

4. Moll J. Can I take statins and grapefruit together. Available at: http://cholesterol.about.com/od/statindrugs/algrapefruitstat.htm. Accessed February 4, 2011.

5. Kajinami K, Takekoshi N, Saito Y. Pitavastatin: Efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. Cardiovascular Drug Reviews. 2003; 21(3): 199-215.

6. HIV Web Study. Drug-Drug Interactions. http://depts.washington.edu/hivaids/drug/case5/discussion.html. Accessed April 9, 2011

7. Ho P, Saville D. Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds. J Pharm Pharmaceut Sci. 2001; 4(3): 217-227.

8. Paine M, Widmer W, Hart H, Pusek S, Beavers K, Criss A, Brown S, Thomas B, Watkins P. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice–felodipine interaction. American Journal of Clinical Nutrition. 2006; 83(5): 1097-1105.

9. Lilja J, Neuvonen M, Neuovonen P. Effects of regular consumption of grapefruit juice on the pharmacokinetis of simvastatin. Br J Clin Pharmacol. 2004; 58(1): 56-60.


11. Ando H, Tsuruoka S, Yanagihara H, Sugimoto K, Miyata M, Yamazoe Y, Takamura T, Kaneko S, Fujimura A. Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin. Br J Clin Pharmacol. 2005; 60(5): 494-497.

QUESTIONS?

kayla jester april 18, 2011 micronutrient metabolism

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