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Nutritional Influence of Drug Metabolism Kim Dalhoff Klinisk farmakologisk afdeling Rigshospitalet DIRAC kursus 4b Torsd

Nutritional Influence of Drug Metabolism Kim Dalhoff Klinisk farmakologisk afdeling Rigshospitalet DIRAC kursus 4b Torsdag den 31. marts 2005. Food-Drug Interactions. Food-Drug Interactions. Therapeutic failure Increased toxicity Pharmacokinetic interactions Pharmacodynamic interactions.

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Nutritional Influence of Drug Metabolism Kim Dalhoff Klinisk farmakologisk afdeling Rigshospitalet DIRAC kursus 4b Torsd

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  1. Nutritional Influence of Drug Metabolism Kim Dalhoff Klinisk farmakologisk afdeling Rigshospitalet DIRAC kursus 4b Torsdag den 31. marts 2005 Food-Drug Interactions

  2. Food-Drug Interactions • Therapeutic failure • Increased toxicity • Pharmacokinetic interactions • Pharmacodynamic interactions

  3. Food-Drug Interactions • Characteristics of the drug • Physical, chemical... • Characteristics of the meal • Size, composition… Fasting (definition) No food intake for at least 1 hour before and at least 2 hours after drug intake

  4. Food-Drug Interactions Pharmacokinetic effect parameters • Bioavailability = Effect • Absorption • First-pass metabolism

  5. Food-Drug Interactions Clinical effect parameters • Depending on the type of drug • E.g. antibacterial, antihypertensive, lipid lowering, anticoagulant...

  6. Food-Drug Interactions • Clinical relevance • Dietary recommendations • Proposed mechanism of interaction • Consequences and qualifications of interaction • Level/grade of evidence Schmidt & Dalhoff. Drugs 2002; 62:1481

  7. Food-Drug Interactions Bisfosfonater ATC M05B Indikationsområde Hyperkalcæmi. Osteolytiske knoglemetastaser. Myelomatose. Paget’s knoglesygdom. Kalcifikation efter columnafrakturer og total hoftealloplastik. Osteoporose. Pamidronat. Ibandronat. Clodronat. Etidronat. Alendronat. Risedronat. Pamidronat.

  8. Food-Drug Interactions Bisfosfonates have an exceptionally high affinity for chelation with dietary divalent cations (Ca2+, Fe2+) Clodronic acid BIO  31 % (½ hr before a meal) Clodronic acid BIO  90 % (with a meal) Clodronic acid BIO  66 % (2 hrs after a meal)

  9. Food-Drug Interactions Other bisfosfonates… • Alendronic acid BIO  85-90 % (+/- 2 hrs of a meal) • Etidronic acid BIO  100 % (with a meal)

  10. Food-Drug Interactions Lipidsænkende midler (statiner) ATC C10A Indikationsområde Ren hypercholesterolæmi samt kombineret hyperlipidæmi Atorvastatin. Fluvastatin. Lovastatin. Pravastatin. Rosuvastatin. Simvastatin

  11. Food-Drug Interactions The various hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have very different chemical and pharmacokinetic properties • Lovastatin BIO  50 % (with a regular meal) • Lovastatin BIO  (ingestion of fibres or fruit) • Pravastatin BIO  31 % (with a regular meal)* • Atorvastatin BIO  (w a r m) • Fluvastatin BIO  (w a r m)

  12. Food-Drug InteractionsConclusion • Some drugs lead to  BIO in the fed state and a risk of treatment failure (tetracycline, indinavir, bisfosfonates…) • A lot of drugs lead to  BIO in the fed state, but no major changes in clinical effect (pravastatin, phenoxymethylpenicillin, furosamide…) • Some drugs lead to  BIO in the fed state and increased drug effect. Usually desirable but may be a risk of toxicity (albendazole, griseofulvin, saquinavir, halofantrine*…)

  13. Food-Drug InteractionsConclusion Other factors… • Dietary habits • Specific diseases • Polyfarmaci • Compliance • Enzyme constitution

  14. Food-Drug InteractionsConclusion • Narrow therapeutic index • Dose titration (TDM) • Hydralazine, tacrolimus, carbamazepine...

  15. De vigtigste…

  16. Grapefruit juice - Drug Interactions DG Bailey et al. Interactions of citrus juices with felodipine and nifedipine. Lancet 1991; 337: 268 M of A: Selective down-regulation of CYP3A4 in the small intestine Nifedipine. Felodipine. Nisoldipine. Nitrendipine. Triazolam. Midazolam. Terfenadine. Cyclosporine.

  17. 200 ml double-strength grapefruit juice 3 times daily for 2 days

  18. Grapefruit juice - Drug InteractionsLipid lowering agents • Lovastatin BIO  1400 % • Atorvastatin BIO  200 % • Simvastatin BIO  1500 % • Pravastatin BIO  * • Fluvastatin BIO  *

  19. Grapefruit juice - Drug InteractionsTerfenadine (antihistamine) • Almost complete presystemic meta-bolism by CYP3A4 • The parent compound has arrhytmo-genic properties (prolongation of QTc interval) • The drug was removed from the US market after a sudden unexpected death of a 29-year old healthy man ascribed to a drug - grapefruit juice interaction

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