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