Download Food-Drug Interactions

Nutritional Influence of
Drug Metabolism
Food-Drug Interactions
Kim Dalhoff
Klinisk farmakologisk afdeling
Rigshospitalet
DIRAC kursus 4b
Torsdag den 31. marts 2005
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 before
and 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 M05B
Indikationsområde
Hyperkalcæmi. Osteolytiske knoglemetastaser.
Myelomatose. Paget’s knoglesygdom.
Kalcifikation efter columnafrakturer og total
hoftealloplastik. Osteoporose.
Pamidronat. Ibandronat. Clodronat.
Etidronat. Alendronat. Risedronat.
Pamidronat.
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)
Food-Drug Interactions
Other bisfosfonates…
• Alendronic acid
BIO  85-90 % (+/- 2 hrs of a meal)
• Etidronic acid
BIO  100 % (with a meal)
Food-Drug Interactions
Lipidsænkende midler (statiner)
ATC C10A
Indikationsområde
Ren hypercholesterolæmi samt kombineret
hyperlipidæmi
Atorvastatin. Fluvastatin. Lovastatin.
Pravastatin. Rosuvastatin.
Simvastatin
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)
Food-Drug Interactions
Conclusion
• 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 Interactions
Conclusion
Other factors…
• Dietary habits
• Specific diseases
• Polyfarmaci
• Compliance
• Enzyme constitution
Food-Drug Interactions
Conclusion
• Narrow therapeutic index
• Dose titration (TDM)
– Hydralazine, tacrolimus,
carbamazepine...
De vigtigste…
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.
200 ml double-strength
grapefruit juice 3 times
daily for 2 days
Grapefruit juice - Drug Interactions
Lipid lowering agents
• Lovastatin BIO  1400 %
• Atorvastatin BIO  200 %
• Simvastatin BIO  1500 %
• Pravastatin BIO  *
• Fluvastatin BIO  *
Grapefruit juice - Drug Interactions
Terfenadine (antihistamine)
• Almost complete presystemic metabolism by CYP3A4
• The parent compound has arrhytmogenic 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
Case story 1
61-year-old man
____________________________
• Orthotopic heart transplantation 11 months earlier
(end-stage ischaemic cardiomyopathy)
• Event free course
• Standard immunosuppressive regimen
Ciclosporin 125 mg x 3
AZA 100 mg x 1
Corticosteroids 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
Ca-antagonister
Expression
Lever, tyndtarm
Karbamazepin
Proteasehæmmere
Modelstoffer
Erytromycin, Midazolam, (Kinidin)
Induktorer
Karbamazepin
Rifampicin
Ciklosporin
Kinidin
Erytromycin
Terfenadin
Tamoxifen
Midazolam
Triazolam
CYP3A4
Inhibitorer
Itrakonazol
Ketokonazol
Erytromycin
Nefazodon
Proteasehæmmere
Grapefrugtjuice