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PHAR 751 Dietary Effects on Metabolism

PHAR 751 Dietary Effects on Metabolism. Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System sbrown@asante.org. Metabolism: P-gp review. Substrate + Inhibitor = Substrate + Inducer = . CYP Metabolism. Cytochrome P450

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PHAR 751 Dietary Effects on Metabolism

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  1. PHAR 751 Dietary Effects on Metabolism Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System sbrown@asante.org

  2. Metabolism: P-gp review • Substrate + Inhibitor = • Substrate + Inducer =

  3. CYP Metabolism • Cytochrome P450 • Gene superfamily: families subfamilies enzyme • Oxidative metabolism – Phase I • Location • Liver • Small intestine • Most abundant P450 is CYP3A4 • Induction = • Inhibition =

  4. Metabolism: CYP review • Substrate + Inhibitor = • Substrate + Inducer =

  5. Food Macronutrients Protein CHO Fats Micronutrients Vitamins Minerals Indoles Drink Grapefruit juice Orange juice Seville orange juice Alcohol  Diet can alter enzyme activity  influence the intensity & duration of action Metabolism & Diet

  6. Macronutrients: Protein Intake • 20% of diet • Malnutrition contributes to variability in drug metabolism • CYP-mediated • In rats: CYP3A activity ↓ from 18% to 1% w/ ↓protein intake • CYP1A2 ↓ w/ 0.5% protein diet • CYP1A1: no change

  7. Protein intake & theophylline metabolism • CYP-mediated • ↓ in Cl of 30% when reduce protein intake from 20% to 10% • ↓ t½ from 8-9 h to 6 h by increasing protein from 10% to 40%. • TPN patients  lower plasma Cl

  8. Another route of metabolism: FMO1 • Flavin-containing monooxygenase (FMO) 1 protein • Oxidative metabolism • Non-inducible • Influenced by dietary intake

  9. Micronutrient: Indole effect on metabolism • Indole-3-carbinol (I3C) • Naturally-occurring chemical found in cruciferous vegetables • Induces CYP1A1 • Inhibits FMO1 • Also marketed as dietary supplement Katchamart, et al. Concurrent flavin-containing monooxygenase down-regulation and cytochrome p-450 induction by dietary indoles in rat: implications for drug-drug interaction. Drug Metabolism and Disposition 2000; 28 (8): 930 – 936.

  10. Influence of dietary I3C on FMO1 protein levels Katchamart, et al. Concurrent flavin-containing monooxygenase down-regulation and cytochrome p-450 induction by dietary indoles in rat: implications for drug-drug interaction. Drug Metabolism and Disposition 2000; 28 (8): 930 – 936.

  11. FMO (-) and CYP (+) Katchamart, et al. Concurrent flavin-containing monooxygenase down-regulation and cytochrome p-450 induction by dietary indoles in rat: implications for drug-drug interaction. Drug Metabolism and Disposition 2000; 28 (8): 930 – 936.

  12. Micronutrient: Indole effect on metabolism of tamoxifen Katchamart, et al. Concurrent flavin-containing monooxygenase down-regulation and cytochrome p-450 induction by dietary indoles in rat: implications for drug-drug interaction. Drug Metabolism and Disposition 2000; 28 (8): 930 – 936.

  13. Why do we care? • Clinical relevance • Drug-drug or drug-food interactions • Potential for altered toxicity of drugs that are substrates for FMO and CYP • Potential altered efficacy (i.e. tamoxifen) • I3C & DIM dietary supplements

  14. Alcohol & Tobacco effects on metabolism • 80 – 95% alcoholics smoke (25 – 30% non-alcoholics smoke) • 70% are heavy smokers • Those who drink & smoke  more cigarettes/day • Correlation between alcohol intake & tobacco use • Association w/ environmental and genetic factors? Schoedel KA, Tyndale RF. Induction of nicotine-metabolizing CYP2B1 by ethanol and ethanol-metabolizing CYP2E1 by nicotine: summary and implications. Biochimica et Biophysica Acta 1619 (2003) 283– 290.

  15. Alcohol & Nicotine: types of tolerance • Tolerance • Cross tolerance • Functional cross-tolerance • Metabolic cross-tolerance Schoedel KA, Tyndale RF. Induction of nicotine-metabolizing CYP2B1 by ethanol and ethanol-metabolizing CYP2E1 by nicotine: summary and implications. Biochimica et Biophysica Acta 1619 (2003) 283– 290.

  16. Alcohol & Nicotine metabolism • Alcohol • Primarily by ADH • 20% by CYP2E1 (up to 60% at high BAC) • Nicotine • Metabolized by CYP2A6 (and CYP2B6 in humans; CYP2B1 in rats ) cotinine (inactive) Schoedel KA, Tyndale RF. Induction of nicotine-metabolizing CYP2B1 by ethanol and ethanol-metabolizing CYP2E1 by nicotine: summary and implications. Biochimica et Biophysica Acta 1619 (2003) 283– 290.

  17. CYP2E1 • CYP2E1 • Also metabolizes APAP, isoniazid, tamoxifen, halothane • Inducible by both EtOH & nicotine • Potential for altering efficacy of clinically used substrates Schoedel KA, Tyndale RF. Induction of nicotine-metabolizing CYP2B1 by ethanol and ethanol-metabolizing CYP2E1 by nicotine: summary and implications. Biochimica et Biophysica Acta 1619 (2003) 283– 290.

  18. Alcohol + Nicotine + CYP2E1 = ? • ↑ expression of CYP2E1 (induced by nicotine and EtOH) • ↑ metabolism of EtOH = metabolic cross-tolerance  more EtOH required for same effect = tolerance Schoedel KA, Tyndale RF. Induction of nicotine-metabolizing CYP2B1 by ethanol and ethanol-metabolizing CYP2E1 by nicotine: summary and implications. Biochimica et Biophysica Acta 1619 (2003) 283– 290.

  19. Study in rats • Up-regulation of brain CYP2B1 & CYP2E1 by EtOH •  Nicotine metabolized by CYP2B1 = metabolic cross tolerance Schoedel KA, Tyndale RF. Induction of nicotine-metabolizing CYP2B1 by ethanol and ethanol-metabolizing CYP2E1 by nicotine: summary and implications. Biochimica et Biophysica Acta 1619 (2003) 283– 290.

  20. Metabolism & Diet √ Food – protein √ Drink – alcohol next: citrus juices

  21. Flavonoids • Naturally occurring in citrus fruits • Known for antioxidant activity • Flavonoids • Flavone • Flavanone • Flavonol • Potential for drug-interactions

  22. PK Study: Felodipine & Grapefruit juice • Substrate: felodipine • Enzyme inhibitor: grapefruit juice • Inhibits CYP3A4 & CYP1A2 • What happens to felodipine concentrations? Lown et al. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression. J Clin Invest. 1997; 99(19): 2545-2553.

  23. Naringin • A flavonoid • Metabolized to the flavonone, naringenin • “bitter” component of grapefruit juice • 800 mg/L • ~100 g flesh = 200 mL regular strength juice • Inhibits CYP3A4 & CYP1A2

  24. Quercetin • A Flavonol • Average daily intake 16 – 25 mg/day • Adjunct to cisplatin, cyclophosphamide, and adriamycin tx • Chelates metal ions; acts as free radical scavenger • ↓ CAD mortality; ↓ stroke incidence • Dietary supplementation: 1 – 1.5 g/day • Known to inhibit oxidation of nifedipine and felodipine

  25. A dihydropyridine calcium channel blocker Reversibly competes w/ other CCBs for dhp-binding sites Blocks voltage-dependent Ca2+ currents in vascular smooth muscle Felodipine

  26. Felodipine + Grapefruit juice • Study: Recurrent administration of grapefruit juice & felodipine kinetics • Hypothesis: continuous administration of grapefruit juice  increased intestinal CYP3A4  diminishing effect on felodipine kinetics Lown et al. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression. J Clin Invest. 1997; 99(19): 2545-2553.

  27. CYP3A4 concentration in study participants • Drop in the CYP3A4 enterocyte concentration in all subjects Lown et al. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression. J Clin Invest. 1997; 99(19): 2545-2553.

  28. ↓ CYP3A4 following GFJ administration Lown et al. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression. J Clin Invest. 1997; 99(19): 2545-2553.

  29. All CYPs? Or just 3A4? “…no consistent change in the level of enterocyte CYP2D6 or CYP1A1 protein with recurrent grapefruit juice ingestion.” Lown et al. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression. J Clin Invest. 1997; 99(19): 2545-2553.

  30. Clinical interactions: felodipine & GFJ ∆ = after 5 days GFJ tid ○ = after first glass GFJ ● = Water Lown et al. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression. J Clin Invest. 1997; 99(19): 2545-2553.

  31. Conclusion: Felodipine + Grapefruit juice • Study: Recurrent administration of grapefruit juice & felodipine kinetics • Hypothesis: continuous administration of grapefruit juice  increased intestinal CYP3A4  diminishing effect on felodipine kinetics • Result: decrease in intestinal CYP3A4 in all subjects Lown et al. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression. J Clin Invest. 1997; 99(19): 2545-2553.

  32. Thursday’s lecture 3/1/07

  33. Terfenadine • Second-generation H1-receptor antagonist • Rapidly and almost completely metabolized by CYP3A4 • Active metabolite • Cardiotoxic drug-drug interactions w/ erythromycin and ketoconazole Benton, et al. Grapefruit juice alters terfenadine pharmacokinets, resulting in prolonged repolarization on the electrocardiogram. Clin Pharmacol Ther. 1996; 59: 383-8.

  34. PK study: Terfenadine & Grapefruit juice • Study: Is bioavailability of terfenadine enhanced by GFJ? • Does timing of terfenadine dose and administration of GFJ matter? Benton, et al. Grapefruit juice alters terfenadine pharmacokinets, resulting in prolonged repolarization on the electrocardiogram. Clin Pharmacol Ther. 1996; 59: 383-8.

  35. PK study: Terfenadine & Grapefruit juice • Primary endpoints: QT prolongation, AUC, Cmax, Tmax • 60 mg terfenadine bid x 7d • + 240 mL GFJ w/ terfenadine x 7d • OR + 240 mL GFJ 2 h after terfenadine dose x 7 d • EKG and plasma level on day 7 and day 14

  36. PK study: Terfenadine & Grapefruit juice A: Simultaneous GFJ administration B: GFJ 2 hours after terfenadine Benton, et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolonged repolarization on the electrocardiogram. Clin Pharmacol Ther. 1996; 59: 383-8.

  37. PD: Terfenadine & Grapefruit juice A: Simultaneous GFJ administration B: GFJ 2 hours after terfenadine Benton, et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolonged repolarization on the electrocardiogram. Clin Pharmacol Ther. 1996; 59: 383-8.

  38. Benton, et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolonged repolarization on the electrocardiogram. Clin Pharmacol Ther. 1996; 59: 383-8.

  39. PK study: Terfenadine & GFJ conclusions • PK interaction: Increases terfenadine concentration in some subjects • Effect more pronounced when administered together • Delayed effect likely d/t rapid absorption of terfenadine • Interaction occurs in gut wall CYP3A enzymes • ↑ concentration  increase in QTc interval on EKG Benton, et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolonged repolarization on the electrocardiogram. Clin Pharmacol Ther. 1996; 59: 383-8.

  40. Another study: Felodipine, water, grapefruit juice • PK of IV and PO felodipine • Grapefruit juice or water 15 min prior to dose of felodipine • 10 mg ER tablet or 1.5 mg IV over 60 min • Measured SBP, DBP, and HR Lundahl J, Regardh CG, Edgar B, Johnsson G. Effects of grapefruit juice ingestion ± pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol. 1997;52:139-145.

  41. PK: Felodipine  IV felodipine w/ water IV felodipine w/ GFJ  PO felodipine w/ GFJ  PO felodipine w/ water Lundahl J, Regardh CG, Edgar B, Johnsson G. Effects of grapefruit juice ingestion ± pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol. 1997;52:139-145.

  42. PK data Lundahl J, Regardh CG, Edgar B, Johnsson G. Effects of grapefruit juice ingestion ± pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol. 1997;52:139-145.

  43. Hemodynamic effects in relation to PK • Oral felodipine + GFJ  ↓ DBP (12 – 19 mmHg); ↓ HR • Effects were similar for IV felodipine w/ water & GFJ Lundahl J, Regardh CG, Edgar B, Johnsson G. Effects of grapefruit juice ingestion ± pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol. 1997;52:139-145.

  44. Hemodynamic data

  45. Study: Felodipine & GFJ conclusions • Metabolism of felodipine occurred in gut wall • Increased plasma concentrations w/ oral felodipine & GFJ  increase hemodynamic effects

  46. Clinical Application • GFJ: ↑ oral availability of commonly used medications • Is the interaction significant?

  47. Grapefruit juice & Seville Orange juice • Furocoumarins • Bergamottin (16 μM GFJ; 5 μM SOJ) • 6’,7’-dihyroxybergamottin (10-60 (23) μM GFJ; 36 μM SOJ) • Bergapten (31 μM SOJ only)

  48. Study: Seville Orange juice, GFJ, & felodipine • Juice  equimolar concentration • Single dose felodipine • Seville orange juice • Dilute GFJ • Common orange juice  (-) control • Hypothesis: furocoumarins are involved in the “grapefruit juice interaction” Malhotra et al. Seville orange juice-felodipine interaction: Comparison with dilute grapefruit juice and involvement of furocoumarins. 2001; 69(1):14-23.

  49. Conc vs. time - felodipine Malhotra et al. Seville orange juice-felodipine interaction: Comparison with dilute grapefruit juice and involvement of furocoumarins. 2001; 69(1):14-23.

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