1. Kayla Jester April 18, 2011 Micronutrient Metabolism

2. 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

3. 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?

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

5. Methodology Grapefruit Juice and Statin Drugs Human research studies within the last 10 years Grapefruit Juice and Cardiovascular Drugs Supplemental Use and Drug Interactions Health Science Library PubMedCinhal

6. 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.

7. 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.

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

9. 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 naringenin 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.

10. 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.

11. 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

12. 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.

13. 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 patheway 10. 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.

14. 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 ExamplePhase 1Phase 2Phase 3Phase 4 Participant GFJ + GFJ+Water+Water + PitavastatinAtorvastatinPitavastatinAtorvastatin 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.

15. 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

16. 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

17. 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

18. 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

19. References 1. Centers for Disease Control ad Prevention. http://www.cdc.gov/MedicationSafety/basics.html. Updated September 24, 2010. Accessed April 5, 2011. 2. 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. 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. 10. 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. 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.

20.  QUESTIONS?