Food-Drug Interactions By Professor: Kamal El din Hussein EL Tahir and Dr.: Dana M. Bakheet Department of Pharmacology, College of Pharmacy, KSU, Riyadh.

Introduction Drugs are chemicals that are used for treatment of diseases. Their actions can be increased or decreased by the concurrent intake of other drugs or food. Such interaction may lead to : a) An Increase or loss of the drug effect or b) An increase in the drug’s Toxicity.

Interactions with Foods Interactions of Foods with Drugs can occur at different sites: a) a) In the stomach (By or pH) Affect the stability of the drugs, e.g Proteins, milk, gelatin …etc can buffer the stomach Acidity

b) In the Intesine: ( i ) Delay, Decrease or Increase of Absorption that occurs via diffusion or Trans porters ( Influx or Efflux types) Influx transporters increase absorption e.g Organic Anion Polypeptides Efflux Transporters increase secretion from intestinal cell into intestinal lumen e.g p-glycoprotein

( i i ) Increase or Decrease of Metabolism via cytochrome P 450: CYP3A4 ( iii ) Adsorption of the Drug e.g pectins ( iv ) Complex formation: e.g Ca with Tetracyclines or penicillamine

(c) Liver increase or decrease of metabolism via Enzymes inhibition or stimulation. increase or decrease of metabolism via Enzymes inhibition or stimulation. (d) Kidney: increase or decrease of Excretion via increase or decrease in urinary pH (f) Drug Action : Increase or decrease of the Beneficial Actions Increase or decrease of the Beneficial Actions Increase or decrease of the side effect & Toxicity Predisposition to Drug - Resistance

Examples of Food-Drugs Interactions 1- Citrus Fruits: (a) Grape Fruit Juice: Active Constituents Geranyl oxy furocoumarin ( µg/ml juice) 2- Naringenin (flavonoid) (0.7mg/ml). 3- Bergamottin (25ng/ml).

Effects on Drugs 1) Bioavailability and t½ (Duration) 2) Peak Blood-level concentration  in Beneficial and Toxic Actions.

(i) Drugs that are Enhanced β – Blockers : Celiprolol, Talinolol Antimalarials : Halofantrine; Quinine Calcium channel Blockers: Verapamil; Nifedipine Felodipine; Nimodipine Nitrendipine; Nisoldipine

Benzodiazepines: midazolam ; Triazolam Antiarrhy thmics: Quinidine; Amiodarone Disopyramide; Propafenone Hypolipoproteinemics: Lovastatin; Simvastatin Atrovastafin Penile vasodilators: Sildenafil; Tadalafil; Vardenafil

Anti – Cancer / Immuno-suppressant: Cyclosporin Antibiotics: Clarithromycin Anti HIV: Saquinavir Oral Hypoglycemics Repaglinide

Anorexiogenics: Sibutramine Cardiac Blockers: Carvedilol Anti – Migraine: Ergotamine

(ii) Drugs that are Inhibited by Grape Fruit Juice Anticancers: Etoposide Angiotensin II Receptor Blocker Losartan Antiplatelets Clopidogrel

Mechanisms of Action: (1) Inhibition of Intestinal and Hepatic CYP450 3A4 " irreversible ” (2) of Transporter P-glycoprotein Dose 250 ml of juice

Problems of Grape Juice Increase in Toxicity of Some Drugs (1)Enhancement of Verapamil – induced Suppression of A – V Conduction (2) in Toxicity of Anti – arrhythmics Amiodarone ; Quinidine Propafenone; Disopyramide ; (3) in Toxicity (Cardiac) of Carvedilol

(4) in Ergotamine – induced gangrene (5) in Hypotensive effects of Vasodilators (6) in Halofantrine – induced Prolongation of Q – T interval (7) in Lovastatin – induced rhabodmyolysis

( 2 ) Orange Juice Consitiuents: Dihydrobergamottin Vitamin C Action: a) Inhibition of Bioavailability of Fexofenadine and Celiprolol Mechamism: Of Influx Transporters Organic Anion Polypeptides b) Decrease in Duration of Action of e.g chloroquine Mechanism: Acidification of urine  increase in Excretion.

3) Tangeretin of Citrus Fruits Action: Blocking of Breast Anticancer Effect of Tamoxifen Mechanism: Reduction in Natural Killer T – Lymphocytes (CD8 + ).

4) Citrus Flavonoids Kaempferol; Quercetin Naringenin Action:decrease of Metabolism of 17β – Oestradiol 5) Citrus aurantium fruit and Citrus grandis pericarp Constituents: Flavonoids Action: increase in cyclosporin bioavailability & Increase in maximum peak Blood level Mechanism: Enhancement of Absorption Inhibition of Intestinal metabolism.

Effect of other foods or Drugs Food Drug Effect 1) 1) Fatty meals Carbamazepine Increase in Bioavailability Praziquantel, Daiazepam, Phenytoin, Lovastatin Theophylline Delay of Absorption Cefaclor // // Indinavir // // Isosorbide mono-nitrate Delay of Absorption due to delay in Gastric emptying Ethambutol Decrease in Absorption Rapamy cin Delay of Absorption Metri fonate Delay of Absorption 2) Vitamin A Isotretinoin Increase in Absorption

Food Drug Effect 3) Coca – Cola Phenytoin Absorption Pepsi – Cola Antihypertensives Effect 4) Honey Carbamazepine Absorption 5) Milk Ciprofloxacin 6) Yoghourt Warfarin in Action 7) Garlic and Antiplatelets onion Hypoglycemics in Action Antihypertesives Anticoagulants 8) Peanut and Antiplatelets sesame oil Anti hypertensives in Action

EffectDrug Food 9) Dietary fibre Digoxin Decrease in Absorption Bran Bran 10) Cheese Tranylcypromine Increase in Action (Tyramine) (MAO – A lnhibitors) Severe Fever & 11) Soyabean Sause Convulsions & Hypertension 12) Foods Fortified with iron and Ca 2 + Tetracyclines with iron and Ca 2 + Tetracyclines Penicillamine in Absorption Penicillamine in Absorption

Food Drug Effect 13) Foods Omeprazole in Action (Full stomach) (Full stomach) lansoprazole lansoprazole Itraconazloe in Bioavailability Itraconazloe in Bioavailability 14) Cran berry Warfarin in Bleeding Juice Juice 15) Vitamin C Basic drugs e.g Pseudoephedrine Excretion e.g Pseudoephedrine Excretion Tetracyclines Absorption Tetracyclines Absorption 16) Millet Carbimazole in Action

17) Tea and coffee Analgesics in Action ( in PGI2) Haloperidol in Action (in metabolism) (in metabolism) Iron in Absorption Iron in Absorption β- Blockers in Action β- Blockers in Action Hydralazine in Action Hydralazine in Action 18) Dates Anti-hyperlipedemics in Action 19) Banana Cimetidine Ranitidine in Action Ranitidine in Action

Food Drug Interaction Licorice Organic nitrate action Organic nitrate action Corticosteroids Retention in Na + +H 2 O Corticosteroids Retention in Na + +H 2 O Fludrocortisone Fludrocortisone Capsicum Antihypertensive in action Cola nut Analgesics in action Ginger Antiplatelets in Bleeding Ginger Antiplatelets in Bleeding

Curcum NSAIDs in activity K + Containing ACEIs Foods Angiotensin Foods Angiotensin Blockers in Hyperkalemia Blockers in Hyperkalemia Cyclosporine Cyclosporine K + Sparing Diuretics K + Sparing Diuretics Other Diuretics in side effects Other Diuretics in side effects

Tea Alkaloids e.g. in activity Atropine Atropine a) High Sodium diet Li + Excretion b) Alfaalfa and Ginger Anticoagulants in Bleeding c) Fenugreek Lovastatin in action ( Antihyperlipedemic effect )

Effect of Drugs on Foods FoodEffect DrugFoodEffect 1) Acarbose Sucrose Absorption of glucose and fructose fructose 2) Fluoxetine Sucrose Absorption Leucine in Absorption ( Transporters) ( Transporters) 3) Metformin Vitamins glucose of Absorption glucose of Absorption 4) Oral Contraceptive Vitamin B6 in Excretion 5) Tetracyclines Ca2+ and and of Absorption and and of Absorption Penicillamine Iron Penicillamine Iron