Nutritional Influence of Drug Metabolism Kim Dalhoff Klinisk farmakologisk afdeling Rigshospitalet...
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Transcript of Nutritional Influence of Drug Metabolism Kim Dalhoff Klinisk farmakologisk afdeling Rigshospitalet...
Nutritional Influence of Drug Metabolism
Kim DalhoffKlinisk farmakologisk afdelingRigshospitalet
DIRAC kursus 4bTorsdag den 31. marts 2005
Food-Drug Interactions
Food-Drug Interactions
• Therapeutic failure• Increased toxicity
• Pharmacokinetic interactions• Pharmacodynamic interactions
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 beforeand at least 2 hours after drug intake
Food-Drug Interactions
Pharmacokinetic effect parameters
• Bioavailability = Effect– Absorption– First-pass metabolism
Food-Drug Interactions
Clinical effect parameters
• Depending on the type of drug– E.g. antibacterial, antihypertensive,
lipid lowering, anticoagulant...
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
Food-Drug Interactions
Bisfosfonater ATC M05BIndikationsområdeHyperkalcæmi. Osteolytiske knoglemetastaser.Myelomatose. Paget’s knoglesygdom.Kalcifikation efter columnafrakturer og totalhoftealloplastik. Osteoporose.
Pamidronat. Ibandronat. Clodronat.Etidronat. Alendronat. Risedronat.Pamidronat.
Food-Drug Interactions
Bisfosfonates have an exceptionally highaffinity for chelation with dietary divalentcations (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)
Food-Drug Interactions
Other bisfosfonates…
• Alendronic acidBIO 85-90 % (+/- 2 hrs of a meal)
• Etidronic acidBIO 100 % (with a meal)
Food-Drug Interactions
Lipidsænkende midler (statiner)ATC C10AIndikationsområdeRen hypercholesterolæmi samt kombinerethyperlipidæmi
Atorvastatin. Fluvastatin. Lovastatin.Pravastatin. Rosuvastatin.Simvastatin
Food-Drug Interactions
The various hydroxymethylglutaryl coenzyme A(HMG-CoA) reductase inhibitors have verydifferent chemical and pharmacokineticproperties
• 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)
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*…)
Food-Drug InteractionsConclusion
Other factors…• Dietary habits• Specific diseases• Polyfarmaci• Compliance• Enzyme constitution
Food-Drug InteractionsConclusion
• Narrow therapeutic index• Dose titration (TDM)
– Hydralazine, tacrolimus, carbamazepine...
De vigtigste…
Grapefruit juice - Drug Interactions
DG Bailey et al. Interactions of citrus juices withfelodipine and nifedipine. Lancet 1991; 337: 268
M of A: Selective down-regulation of CYP3A4 inthe small intestine
Nifedipine. Felodipine. Nisoldipine. Nitrendipine.Triazolam. Midazolam. Terfenadine.Cyclosporine.
200 ml double-strengthgrapefruit juice 3 timesdaily for 2 days
• Lovastatin BIO 1400 %• Atorvastatin BIO 200 %• Simvastatin BIO 1500 %• Pravastatin BIO *• Fluvastatin BIO *
Grapefruit juice - Drug InteractionsLipid lowering agents
• 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
Grapefruit juice - Drug InteractionsTerfenadine (antihistamine)
Case story 161-year-old man____________________________• Orthotopic heart transplantation 11 months earlier
(end-stage ischaemic cardiomyopathy)• Event free course• Standard immunosuppressive regimen
Ciclosporin 125 mg x 3AZA 100 mg x 1Corticosteroids 7½ mg x 1
• Ciclosporin plasma levels stable• 3 weeks before admission St J wort because of mild
depression(Jarsin® 900 g hypericin x 3 daily)
F Ruschitzka et al. Lancet 2000; 355: 548
Karbamazepin
Ca-antagonister
Kinidin
Protease-hæmmere
Erytromycin
Ciklosporin
CYP3A4
ExpressionLever, tyndtarm
ModelstofferErytromycin, Midazolam, (Kinidin)
InduktorerKarbamazepinRifampicin
InhibitorerItrakonazolKetokonazolErytromycinNefazodonProteasehæmmere
Grapefrugtjuice
Terfenadin
Tamoxifen
MidazolamTriazolam