1 / 59

Grapefruit Juice-Drug Interaction

Grapefruit Juice-Drug Interaction. Paul F. Cancalon. Florida Department of Citrus. http://www.wlap.org/wl-repository/umich/cacr/grand-rounds/20031202-annarbor-01-watkins/real/sld011.htm. P. B. Watkins 2003. Drug Taken with GJ. Drug Blood Concentration (AUC). Drug Taken without GJ. Time.

landry
Download Presentation

Grapefruit Juice-Drug Interaction

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Grapefruit Juice-Drug Interaction Paul F. Cancalon Florida Department of Citrus

  2. http://www.wlap.org/wl-repository/umich/cacr/grand-rounds/20031202-annarbor-01-watkins/real/sld011.htmhttp://www.wlap.org/wl-repository/umich/cacr/grand-rounds/20031202-annarbor-01-watkins/real/sld011.htm P. B. Watkins 2003

  3. Drug Taken with GJ Drug Blood Concentration (AUC) Drug Taken without GJ Time

  4. P. B. Watkins 2003

  5. Cytochrome P450

  6. Cytochrome P450 Definition Cytochrome P450 enzymes are a superfamily of more than 160 known members that play a major role in the metabolism a wide array of xenobiotics including drugs, chemical carcinogens, insecticides, petroleum products, and other environmental pollutants. Although the liver is the primary organ for drug metabolism, extrahepatic tissues such as lung, kidney and intestine, also play an important role for detoxification or biotransformation of xenobiotics. Each tissue has a unique P450 isozyme distribution and regulatory mechanism for cytochrome P450 gene (CYP) expression.

  7. Cytochrome P450 Naming classification: CYP 3 A 4 *15 A-B family>40% sequence-homology isoenzyme allele sub-family>55% sequence-homology J R Oesterheld : Drug-Drug Interactions

  8. Model of rat P450 2B1, showing mode of membrane attachment home.ccr.cancer.gov

  9. Lock/Key or Enzyme/Substrate Reaction

  10. Irreversible Inhibition

  11. P-Glycoprotein

  12. Cell Membrane

  13. P Glycoprotein Blockage www.biotechjournal.com

  14. Furanocoumarins P450 Interactions

  15. Furanocoumarins as potent chemical defenses Furanocoumarins are toxic compounds found primarily in species of the Apiaceae and Rutacea.  They come in a variety of flavors and have adverse affects on wide variety of organisms, ranging from bacteria to mammals.  Some of the furanocoumarins are photoactive--their toxicity is enhanced in the presence of ultraviolet radiation..  The furanocoumarins found in wild parsnip play a dominant role in resistance of this plant to its principal enemy the parsnip webworm

  16. Peter Kareiva May R. Berenbaum Two potential outcomes of a coevolutionary interaction are an escalating arms race • Diversification of cytochrome P450 monooxygenases (P450s) is thought to result from antagonistic interactions between plants and their herbivorous enemies

  17. Grapefruit Furanocoumarins

  18. The immediate precursors for furanocoumarin synthesis are umbelliferone and isoprene.  Two categories of furanocoumarins are produced; the linear furanocoumarins have the furan ring in line with the benz-2-pyrone nucleus, while the angular furanocoumarins have the furan ring oriented at an angle to the nucleus.

  19. Bergapten Bergaptol O O O O Bergamottin 6,7-Epoxybergamottin 6,7-DHB

  20. O O H O O O O O H O O O O Paradisin C Paradisin A

  21. P. B. Watkins 2003

  22. Bergamotin Spiro3,FC726,Paradisin 3-4FC ? Bergaptol Up to 10 Spiroesters ? 6,7 DHB FC ? FCs ? FC ?

  23. Bergaptol

  24. Bergaptol Geranyl side chain Bergamottin

  25. Bergaptol 6,7-DHB

  26. O O H O O O O O H O O O O Spiroester3 Spiro3 Bergaptol

  27. The order of inhibitory potency of these compou nds was FC726>6,7DHBG> bergamottin > bergapten > bergaptol O O Ohnishi A et al. : Br J Pharmacol . 2000 Jul;130(6):1369 - 77. O O O O O O O O O O O O O O O O H H O O H O O H O O O H bergapten O O O O > > > > bergaptol 6,7 DHB bergamottin Paradisin A (Spiro 3)

  28. Drug Bioavailability

  29. Uptake of orally administered drug proceeds after the stomach passage via the small intestine. In the gut and liver, a series of metabolic transformation occurs. J R Oesterheld : Drug-Drug Interactions

  30. www.siumed.edu/~dking2/ erg/images arbl.cvmbs.colostate.edu/.../ smallgut/villus

  31. Site of Action of Some Drugs Affected by Grapefruit Juice

  32. Calcium channel blockers Target Blocked - calcium channel blockers in actionwww.thediabetesvillage.com

  33. Calcium channel blockers • decreases contractility in myocardial cells and tone in vascular smooth muscle www.soton.ac.uk

  34. Drug- Grapefruit Juice Interaction

  35. P. B. Watkins 2003

  36. P. B. Watkins 2003

  37. Time-course of recovery of CYP3A function after single doses of grapefruit juice. Greenblatt DJ, von Moltke LL, Harmatz JS, Chen G, Weemhoff JL, Jen C, Kelley CJ, LeDuc BW and Zinny MA. Clinical Pharmacology and Therapeutics 2003;74:121-12 Liver microsome method micro.magnet.fsu.edu

  38. Paradisin C: a new CYP3A4 inhibitor from grapefruit juice Tetrahedron 58 (2002) 6631-6635Tetrahedron 58 (2002) 6631-6635 CYP3A4 inhibition assay CYPP3A4 activity is based on nifedipine oxidation. 100 mM phosphate buffer (pH 7.4) containing 50 uM nifedipine 5 mM glucose-6-phosphate, 0.5 mM 3-NADP+, glucose-6phosphate dehydrogenase. CYP3A4 is preincubated in 7 uL of the buffer at 37EC for 5 min and added to the sample solution The solution is incubated at 37EC for 1 h. The residue is analyzed by reverse phase HPLC for the nifedipine metabolite (nifedipine pyridine), and for nifedipine. The value of IC50, the concentration required for 50% inhibition of CYP3A4 activity.

  39. Drug Drug Drug Drug Liver 10% CYP3A4 100% 20% CYP3A4 80% 10% CYP3A4 Target over 90% of saquinavir is metabolized by the cytochrome P450 isoenzyme CYP3A4 {01} . Saquinavir is thought to undergo extensive first-pass metabolism and is rapidly metabolized to a variety of inactive mono- and di-hydroxylated compounds Small Intestine

  40. Drug Drug Drug Drug CYP3A4 Drug Enterocytes 100% Nucleus 30% 70% ? P Glycoprotein Villus

  41. FC Drug Drug Drug Drug FC CYP3A4 Enterocytes 100% Nucleus 70% 30% X P Glycoprotein ? Villus

  42. FC CYP3A4 FC Nucleus Competitive Enzyme/Substrate Binding Enterocyte From: P. B. Watkins 2003

  43. CYP3A4 FC Metab FC Metab FC Metab Nucleus Enzymatic Metabolism of FC (1h) Enterocyte From: P. B. Watkins 2003

  44. FC Metab CYP3A4 FC Metab FC Metab Nucleus Protein Catabolism Enterocyte CYP3A4 Tagging and Destruction (3D) From: P. B. Watkins 2003

  45. P. B. Watkins 2003

  46. Variation of Enterocyte CYP3A4 Activity And the Oral Distribution of Substrates 10 Drug Blood Concentration CYP3A4 Activity 0 Time CYP3A4 Distribution in Human Population From: P. B. Watkins 2003

  47. P. B. Watkins 2003

More Related