Food-Drug-Nutrient Interactions

Overview
Of almost 900 drugs and fixed-drug combinations used in the US: Almost 400 may deplete specific nutrients Over 400 may interact with food or food components Over 300 have been shown to interact with dietary supplements, with adverse and beneficial interactions equally common

Definition of Terms
Drug-nutrient interaction: the result of the action between a drug and a nutrient that would not happen with the nutrient or the drug alone Drug-food interaction: a broad term that includes drug-nutrient interactions and the effect of a medication on nutritional status

Food-Drug Interaction
For example, a drug that causes chronic nausea or mouth pain may result in poor intake and weight loss

Key Terms
Bioavailability: degree to which a drug or other substance reaches the circulation and becomes available to the target organ or tissue; % free to function Absorption rate: % absorbed and time for absorption Half-life: amount of time it takes for the blood concentration of a drug to decrease by one half of its steady state level Transported: amount in blood (free or bound) Metabolized: altered by enzymes in tissues Side effect: adverse effect/reaction or any undesirable effect of a drug

Types of Drug Interactions

1. Decreased bioavailability of drug
Absorption (fibers, mucilage herbs, pglycoprotein) Metabolism ( CYP 450) Elimination (laxative or diuretic herbs)

2. Increased bioavailability of drug

Absorption (Ginger, Cayenne, Black Pepper) Metabolism ( CYP 450, eg. Grapefruit Juice) Elimination (Licorice - anti-diuretic)

Types of Drug Interactions

3. Potentiation of drug via similar activity
Example: Drug diuretic and herb diuretic

Types of Interactions
Pharmacokinetics Movement of drugs through the body by Absorption Distribution Metabolism (enzymatic transformation ) Excretion Most adverse interactions are of this type

4. Potentiation of drug via complementary activity

Example: Gymnema, vanadium, etc. and insulin or oral hypoglycemics

5. Reduced side effects of drug

Positive interaction Example: Milk Thistle and hepatotoxic drugs

Absorption
Movement of the drug from the site of administration to the bloodstream; depends on
The route of administration The chemistry of the substance and its ability to cross membranes The rate of gastric emptying and GI movement The quality of the product formulation

Distribution
When the drug leaves the systemic circulation and moves to various parts of the body Drugs in the bloodstream are often bound to plasma proteins; only unbound drugs can leave the blood and affect target organs Low serum albumin can increase availability of drugs and potentiate their effects

Food, food components (fiber, fatty acids, etc) and nutritional supplements can interfere with absorption

Metabolism (biotransformation)
Cytochrome P-450 enzyme system facilitates drug metabolism Foods or dietary supplements that increase or inhibit these enzyme systems can change the rate or extent of drug metabolism

Excretion
Drugs are eliminated from the body as an unchanged drug or metabolite
Renal excretion the major route of elimination; affected by renal function and urinary pH Some drugs eliminated in bile and other body fluids

Pharmacokinetic Mechanisms
Alteration of gastrointestinal or urinary pH Stimulation, induction or inhibition of enzymes involved in biotransformation or transport of drugs or nutrients Displacement of a drug from binding to plasma proteins Alteration of solubility

Pharmacodynamics
Pharmacodynamic: two substances exhibit pharmacologic actions that reinforce or interfere with each others actions Physiologic and biochemical effects of drug combining Know: the mechanism of action, e.g. how a drug works Often the drug molecule binds to a receptor, enzyme, or ion channel, producing a physiological response

Biopharmaceutics Classification System for drugs

Pharmacogenomics, Nutrigenomics
Genetically determined variations that are revealed solely by the effects of drugs Affect a subset of people (that we know of) Examples include G6PD (glucose-6-phosphate dehydrogenase) enzyme deficiency, warfarin resistance, and slow inactivation of isoniazid (IHN) or phenelzine

G6PD (glucose-6-phosphate dehydrogenase) enzyme deficiency

X-chromosome-linked, Also called favism Most common in African, Middle Eastern, and Southeast Asians Fava beans or pollen, Vitamin K or Vitamin C can cause hemolysis Can lead to neonatal jaundice, hemolytic anemia or acute hemolysis

Slow CYP2D6 Metabolizers

CYP2D6 and CYP2C19 metabolize 25% of drugs including many antidepressants, antipsychotics, and narcotics Slow metabolizers at risk for toxicity and adverse drug effects Fast metabolizers have unpredictable response Drug genotyping in future will help determine most effective meds for individuals Goldenseal significantly inhibits CYP2D6 and may lead to significant herb-drug-CYP2D6 interactions when given with drugs metabolized by the CYP2D6 enzyme
Gurley BJ, et al. . Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea. Mol Nutr Food Res. 2008 Jul;52(7):755-63

Therapeutic Importance
Therapeutically important interactions are those that: Alter normal nutritional status cause depletions, or higher amounts of nutrients Alter the intended response to the medication Cause drug toxicity Reduce drug toxicity Who is at risk? Special populations Patients with chronic disease: DM, HIV, CVD Patients with atopy Malnourished patient

Risk Factors
Polypharmacy (including nutritional and herbal supplements) Special diets Alcohol intake Drugs of abuse Non-nutrients in foods Excepients in drugs or food

Malnutrition Effect on Drugs

Low albumin levels can make drugs more potent by increasing availability to tissues
Lower doses often recommended for persons with low albumin Warfarin and phenytoin are highly protein bound in blood; albumin can result in poor seizure control (phenytoin) or hemorrhage (warfarin)

Fiber
Phytates in grains and fiber supplements can inhibit the absorption of minerals, especially Cu, Zn, and Mn but also Mg and Fe Calcium when pH is above 4 And can interfere with absorption of digoxin, lithium, penicillin, and some antidepressants

Body composition: obese or elderly persons have a higher ratio of adipose tissue; fat soluble drugs may accumulate in the body risk of toxicity

Fat soluble vitamins

Absorption may be reduced by high amounts of PUFAs, increased with SF Drugs that interfere with fat absorption (ie interact with bile, bile-acid sequestrants [cholesterol-lowering medications such as colestipol, colesevelam, and cholestyramine]) decrease fat soluble vitamin absorption Most fibers decrease absorption

Vitamin A
Chronic alcohol consumption results in depletion of liver stores of vitamin A, and may contribute to alcoholinduced liver damage Oral contraceptives increase retinol binding protein (RBP) synthesis by the liver, increasing the export of RBPretinol complex in the blood Vit E necessary for conversion of B-carotene to retinol and protects both from oxidation Vit E is also necessary for Vit A transport and storage Vit A def. Fe mobilization microcytic anemia Zn def. affect mobilization of vitamin A from hepatic stores and absorption of vitamin A from the gut

Vitamin A: positive interactions

Antacids: coadministration exerts protective effect and enhances healing of gastric ulcers. Anthelmintic drugs: def. ass. w/ inc infections, coadministration can increase healing Cholestyramine: bile acid sequestrants tend to reduce absorption and assimilation of vitamin A and other fat-soluble nutrients Cancer: increased therapeutic effect with alkylating agents ie cyclophosphamide, Decreased toxicity with antibiotic-type agents ie doxorubicin

Vitamin A: Negative interactions

Colchicine: may impair absorption Statin therapy: may elevate serum retinol levels, possibly by altering liver function Neomycin: oral, particularly high doses over extended periods, may impair vitamin A absorption Tetracycline antibiotics: associated with severe adverse effects, particularly headaches and pseudotumor cerebri (benign intracranial hypertension). Effects may be sudden and severe.

Vitamin A
Hypervitaminosis A: has been reported to have happened with as little as 20, 000 for a few weeks But doses as high as 500,000 for several years has also been reported NOT causing problems Not recommended to combine with synthetic retinoids

Hypervitaminosis A: Risk factors for osteoporosis

One theory: stimulates bone resorption and inhibits bone formation Hypercalcaemia and bone abnormalities High A may interfere with both Vit D & E
Chem Biol Interact. 2006 Jan 5;159(1):73-80. Epub 2005 Nov 9. Diane Feskanich et al. Vitamin A Intake and Hip Fractures Among Postmenopausal Women. JAMA: The Journal of the American Medical Association 287 (1), 47-54 (02 Jan 2002)

Vitamin D: positive
Allopurinol: may elevate serum conc. of 1,25(OH)2-vitamin D3 by reducing uric acid's inhibition of 1-hydroxylase activity Bisphosphonates: Synergistic interaction, Coadminister vitamin D; administer calcium but separate intake from bisphosphonates. HRT: Synergistic interaction, especially with osteoporosis Raloxifene: Synergistic interaction

Vitamin D: negative
Anticonvulsant medications: Phenytoin and phenobarbital accelerate vitamin D metabolism in liver (CYP450 induction) and may reduce serum levels of 25(OH)D Thioridazine: inhibits hepatic cytochrome P2D6 and may decrease the metabolism Verapamil/ Calcium channel blockers: increase calcium availability, which opposes verapamil's activity as calcium antagonist. Excess vitamin D might theoretically contribute to hypercalcemia on rare occasions, which in turn might theoretically precipitate cardiac arrhythmia in patients

Vitamin D: negative
The oral anti-fungal medication, ketoconazole, inhibits the 25(OH)D3-1-hydroxylase enzyme and has been found to reduce serum levels of 1,25(OH)D in healthy men Pb D3 activation Renal disease, Phosphate (+) plasma D3

Vitamin E
Estrogens increase the body's Vitamin E requirements Alcohol (ethanol) destroys Vitamin E
Bjorneboe, G. A., et al. Diminished serum concentration of vitamin E in alcoholics. Annals of Nutrition and Metabolism. 32:56-61, 1988.

Tobacco smoking lowers the bodys Vitamin E content.

Handelman GJ et al. Destruction of tocopherols, carotenoids, and retinol in human plasma by cigarette smoke. Am J Clin Nutr. Apr;63(4):559-65. 1996

Fe2+ Vit E efficiency PUFAs, EFAsvit E requirements

Vitamin E: positive
Glyburide: can reduce lipid peroxidation and may enhance glycemic control and improve insulin action Omeprazole/Proton pump inhibitors: may reduce esophagitis and support omeprazole therapy by increasing the mucosal resistance to oxidative damage from gastroesophageal reflux Cyclosporine: may potentiate ASA

Aspirin-Vitamin E Interactions
a-Tocopherol (50 IU/day) raised risk of gingival bleeding 25% among ASA users 400 IU/day a-tocopherol added to 325 mg ASA/day reduced incidence of TIAs compared to aspirin alone Vit E 50 IU/day, decreased ischemic stroke by 30% but increased hemorrhagic stroke by 145% in hypertensive, non-diabetic male smokers. In diabetics, there was no increase in hemorrhagic stroke and ischemic stroke decreased by 70%.

Vitamin E: negative
Bile acid sequestrants Gemfibrozil: may reduce serum levels of alpha- and gamma-tocopherol, and other antioxidants Haloperidol: Free radical production and oxidative damage caused by haloperidol contribute to tardive dyskinesia and other adverse effects, and may be due, to some degree, to drug-induced vitamin E depletion

Vitamin E and Statins

a-Tocopherol prevents statin benefits in people with low HDL-C and normal TC Related to tocopherol inhibition of statininduced elevation of HDL2-C Selenium (100 mcg/day) and fish oil have the opposite effect a-Tocopherol depletes gamma-tocopherol by competitive binding to transport protein

Statins
Statin-induced Co10-Q depletion impairs mitochondrial function, raising the serum lactate/pyruvate ratio Statin-induced Co-Q depletion is increased by vitamin E (700 IU/day) - Co-Q is consumed in recycling tocopheryl quinones back to tocopherols

Statins
Beta-Carotene Carnitine Coenzyme Q10 Garlic Gotu Kola Niacin Omega-3 Fatty Acids Policosanol Reishi Selenium St. John's Wort Vitamin A Niacin Vitamin C Vitamin E

Vitamin E and Warfarin

High-dose vitamin E may enhance effect of coumadin-derivative anticoagulants by decreasing vitamin K levels and activity, reflected by PIVKA-II, an underactive form of prothrombin produced in presence of vitamin K insufficiency

Warfarin Interactions
49 natural products may interfere with warfarin; 21 confirmed, 28 possible Herbal coumarins might compete for binding to plasma protein, increasing plasma free warfarin concentration Some controlled studies have found no effect on vitamin E or coenzyme Q10 on INR of patients taking warfarin

Vitamin K
Required for Prothombin, Factors IX, VII and X Produced endogenously by bacterial flora, greens Coumadin/Warfarin competes with Vit K at cellular binding sites to thin blood: recommendations for one salad a day Salicylates increase need for Vit K (when used for pain, not blood thinning) Large doses of vitamin A and vitamin E have been found to antagonize vitamin K

Vitamin K
Antibiotics: can inhibit or eliminate beneficial intestinal flora, thus disrupting gut ecology and interfering with endogenous vitamin K2synthesis Oral corticosteroids can cause increased urinary loss of vitamin K as well as depletion of other key nutrients

Coenzyme Q 10
Similar structure as vitamin K Same conditions as fat soluble nutrients better with fat in meal (and is also available lipid based) Piperine increases absorption by 30% May potentiate warfarin Increased need with HMG COA reductase drugs, Tricyclic antidepressants, Beta Blockers

Corticosteroids
Calcium and Vitamin D: Oral corticosteroids have shown clinically to reduce absorption of calcium and interfere with the activation and metabolism of the vitamin D increasing the risk of bone loss This is of particular concern for anyone who is maintained on long-term steroids Magnesium - Corticosteroids may increase the bodys loss

Corticosteroids
Chromium: Preliminary data suggest that corticosteroid treatment increases chromium loss and that supplementation with chromium (600 mcg per day in the form of chromium picolinate) can prevent corticosteroidinduced diabetes Sodium: steroids can cause both sodium and water retention Potassium: increase urinary loss Vitamin B6: may increase the loss of vitamin B6 Other nutrients: Oral corticosteroids have been found to increase urinary loss of vitamin K, vitamin C, selenium, and zinc; and deplete Vitamin C and Taurine

Oral corticosteroids
Calcium Cayenne Chromium DHEA Echinacea Ephedra Folic Acid Horse Chestnut Licorice Magnesium Melatonin Omega-3 Fatty Acids Potassium Selenium Taurine Vitamin A Vitamin B6 Vitamin C Vitamin D Vitamin K Zinc