Food-Drug Interactions

Food-Drug Interactions
Drug-Nutrient Interactions Nutrient-Drug Interactions

Types of Interactions Drug-Nutrient Interactions
Effect of a medication (Both prescription and OTC medications ) on food or a nutrient in food Nutrient-Drug Interactions Effect of food or a nutrient in food on a medication Types on Interactions A Drug-Nutrient Interaction is the effect of a medication on food or a nutrient in food. A Nutrient-Drug Interaction is the effect of food or a nutrient in food on a medication. How Drugs and Nutrients Interact Both prescription and over-the-counter medications can affect the way your body uses nutrients in food. In addition, certain foods or nutrients in food can affect the action of medication. A drug-nutrient interaction refers to the effect of a medication on food or a nutrient in food. Medications interact with foods and nutrients in several ways. Medications can decrease appetite or change the way a nutrient is absorbed, metabolized, or excreted. A nutrient-drug interaction refers to the effect of food or a nutrient in food on a medication. Dietary nutrients can affect medications by altering their absorption or metabolism. The food you eat could make the medications you take work faster, slower, or even prevent them from working at all. Drug Nutrient Nutrient Drug

Therapeutic Importance
Therapeutically important interactions are those that: Alter the intended response to the medication Cause drug toxicity Alter normal nutritional status

Benefits of Minimizing Food Drug Interactions
Medications achieve their intended effects Improved compliance with medications Less need for additional medication or higher dosages Fewer caloric or nutrient supplements are required Adverse side effects are avoided

Benefits of Minimizing Food Drug Interactions
Optimal nutritional status is preserved Accidents and injuries are avoided Disease complications are minimized The cost of health care services is reduced There is less professional liability Licensing agency requirements are met مسئولیت حرفه ای

Nutrition Implications
Little chance taking a medication for a short time will affect your nutritional status However, using some medications for months or years may affect your nutritional health Changing diet to include more foods rich in vitamins and minerals is preferred to taking vitamin or mineral supplements Nutrition Implications Such interactions raise concerns that medications may lead to nutritional deficiencies or that your diet may change how a medication works. There is little chance that taking a medication for a short time, such as a ten day treatment, will affect your nutritional status. However, use of some medications for months or years may affect your nutritional health. This does not mean that if you are taking a medication you need to use a vitamin and or mineral supplement. Changing diet to include more foods rich in vitamins and minerals is preferred to taking vitamin or mineral supplements. In fact, vitamin and or mineral supplements taken in excess can affect how a medication works.

Drug-Nutrient Interactions
Medications, can affect nutrients by: Decreasing food intake Decreasing nutrient absorption Slowing down nutrient production Interfering with nutrient metabolism Increasing nutrient excretion Drug-Nutrient Interactions Medications, both prescription and over-the-counter, can affect how the body uses nutrients. For individuals taking medications for long periods of time drug-nutrient interactions may lead to vitamin or mineral deficiencies. Medications, can affect nutrients by: Decreasing food intake Decreasing nutrient absorption Slowing down nutrient production Interfering with nutrient metabolism Increasing nutrient excretion

Drug-Nutrient Interactions: Food Intake
Some medications can affect nutritional health by causing poor food intake due to: Decreased appetite Nausea or vomiting Unpleasant taste or dry mouth Gastrointestinal sores or inflammation Decrease food intake: Some medications can affect nutritional health when they cause decreased appetite; interfere with taste or smell; cause nausea or vomiting; cause unpleasant taste or dry mouth; cause sores or inflammation which results in pain or discomfort when eating. This can affect nutritional health by causing poor food intake. These types of complications are only significant to nutritional health when they continue for a long time. However, nutritional health can be affected if decreased food intake persists

Drug-Nutrient Interactions: Food Intake
Examples: Appetite suppressants are medications which affect food intake by depressing appetite Several cancer medications and treatments may dramatically reduce food intake by causing: Loss of appetite Changes in taste perception Nausea, vomiting Dry mouth Mouth and intestinal sores or inflammation Decreased food intake: Example: Appetite suppressants are medications which directly affect food intake by depressing appetite. Example: Amphetamines can change taste perception. Example: Some antidepressants may cause dry mouth. Example: Several cancer medications and treatments may cause loss of appetite, changes taste perception, nausea, vomiting, dry mouth or sores dramatically reducing food intake.

Drugs Affecting Oral Cavity, Taste and Smell
Taste changes: cisplatin, captopril (anti- hypertensive) amprenavir (antiviral) phenytoin (anti-convulsive), clarithromycin (antibiotic) Mucositis: antineoplastic drugs such as interleukin-2, paclitaxel, carboplatin Dry mouth: Anticholinergic drugs (tricyclic antidepressants such as amytriptyline, antihistamines such as diphenhydramine, antispasmodics such as oxybutynin

Chemotherapy-Induced Oral Mucositis
Oral complications of Radiotherapy

2- Drug-Nutrient Interactions: Nutrient Absorption
Some medications can affect nutritional health by decreasing nutrient absorption due to: Decreasing time in intestine Altering stomach acidity Damaging intestinal lining Competing for absorption Binding nutrients Decrease nutrient absorption: Some medications can affect nutritional health by decreasing the absorption of nutrients. Medications can decrease nutrient absorption by decreasing the time nutrients are in the intestine, changing the acidity of the digestive tract, damaging the lining of the intestine, competing for absorption or binding to nutrients.

2- Drug-Nutrient Interactions: Nutrient Absorption
Examples: Laxatives can cause food to move rapidly through the intestinal track which can decrease nutrient absorption Antacids can lower stomach acidity which can may interfere with iron, folate and vitamin B12 absorption Many cancer medications and treatments can damage the intestinal lining which can decrease nutrient absorption Decrease nutrient absorption: Example: Laxatives can decrease the absorption of many vitamins and minerals. Laxatives cause food to move rapidly through the body causing poor nutrient absorption. Example: Antacids lower stomach acidity and may interfere with iron, folate and vitamin B12 absorption Example: Several cancer medications and treatments damage the lining of the intestine decreasing nutrient absorption.

2- Drug-Nutrient Interactions: Nutrient Absorption (cont.)
Examples: Some anticonvulsants can compete for absorption with folate resulting in decreased folate absorption Some cholesterol lowering medications reduce cholesterol by removing bile acids Bile acids are needed to absorb essential fatty acids and fat-soluble vitamins As a result some cholesterol lowering medications can reduce absorption of fat-soluble nutrients Decrease nutrient absorption (cont.): Example: Some anticonvulsants can decrease folate absorption. Example: Some cholesterol lowering medications reduce cholesterol by removing bile acids. Bile acids are needed to absorb the fat-soluble vitamins A, D, E, and K. As a result some cholesterol lowering medications can reduce absorption of fat-soluble vitamins.

3- Drug-Nutrient Interactions: Nutrient Production
Some medications can affect nutritional health by slowing down nutrient production Vitamin K produced by bacteria in the intestine Antibiotics kill harmful bacteria, but they can also kill helpful bacteria , Killing helpful vitamin K producing bacteria can result in decreased vitamin K production Decrease nutrient production: Some medications can affect nutritional health by slowing down the production of nutrients.

4- Drug-Nutrient Interactions: Nutrient Metabolism
Some medications can affect nutritional health by interfering with body’s ability to metabolize nutrients due to: Affecting enzyme systems Competing with enzyme systems Interfere with nutrient metabolism: Some medications can affect nutritional health by interfering with the body’s ability to metabolize nutrients. Some medications use similar enzyme systems or compete for carriers in the body.

4- Drug-Nutrient Interactions: Nutrient Metabolism
Examples: Some anticonvulsants alter liver enzyme activity causing increased metabolism of folate, vitamin D, and vitamin K Methotrexate resembles folate in structure and competes with enzymes that converts folate to its active form, this can result in folate deficiency Interfere with nutrient metabolism: Example: Methotrexate resembles folate in structure and competes with the enzyme that converts folate to its active form. Use of methotrexate can cause folate deficiency. Example: Some anticonvulsants alter the activity of liver enzymes causing increased metabolism of folate, vitamin D, and vitamin K.

5- Drug-Nutrient Interactions: Nutrient Excretion
Some medications can affect nutritional health by increasing nutrient excretion due to: Decreased kidney reabsorption Increased urinary excretion Increase nutrient excretion: Some medications can affect nutritional health by increasing nutrient excretion. Some medications can affect mineral reabsorption by the kidneys or increase nutrient losses by increasing urinary excretion.

5- Drug-Nutrient Interactions: Nutrient Excretion
Diuretics remove excess fluid from the body Some diuretics may also increase loss of potassium along with fluids Large amounts of aspirin can cause increased loss of folate Isoniazid, an antituberculosis medication, is similar in structure to vitamin B6 and induces vitamin B6 excretion Since treatment is for 6 months, B6 supplements are routinely given to prevent deficiency Increase nutrient excretion: Example: Diuretics remove excess fluid from the body. Some diuretics may also increase loss of potassium along with fluids. Potassium is very important in proper functioning of the heart and other muscles. Example: Large amounts of aspirin can cause increased loss of folate. Also, large amounts of aspirin over long periods of time may cause stomach bleeding that could result in iron deficiency. Over time iron deficiency can lead to anemia. Diuretics remove excess fluid from the body Some diuretics may also increase loss of potassium along with fluids Potassium is very important in proper functioning of the heart and other muscles Large amounts of aspirin can cause increased loss of folate

Food-Drug Interactions
Some foods or nutrients in food can also alter a medication’s effectiveness by: Decreasing medication absorption Interfering with medication metabolism Interfering with medication removal Food-Drug Interactions Food and nutrients can also alter a medication's effectiveness in many ways such as: Decreasing medication absorption Interfering with medication metabolism Interfering with medication removal

Absorption Movement of the drug from the site of administration to the bloodstream; depends on The route of administration The chemistry of the drug and its ability to cross membranes The rate of gastric emptying (for oral drugs) and GI movement The quality of the product formulation Food, food components and nutritional supplements can interfere with absorption, especially if the drug is taken orally

Nutrient Interactions: Medication Absorption
Some foods or nutrients in food can increase or decrease medication absorption by: Decreasing stomach emptying Binding to medications Competing for absorption Altering acidity Decreasing medication absorption: Food or nutrients in food can increase or decrease the absorption of a drug by: Decreasing stomach emptying rate Binding to medications Competing for absorption Altering acidity Effectivness overdose effect the intended dose

Food/Nutrient Effects on Drugs
Absorption Presence of food and nutrients in intestinal tract may affect absorption of drug Antiosteoporosis drugs Fosamax or Actonel: absorption negligible if given with food; ↓ 60% with coffee or orange juice

Absorption Absorption of iron from supplements ↓↓ 50% when taken with food Best absorbed when taken with 8 oz of water on empty stomach Food may ↓↓ GI upset If take with food, avoid bran, eggs, fiber supplements, tea, coffee, dairy products, calcium supplements

Medications are typically absorbed more quickly when the stomach is empty (1 hour before or 2 hours after eating) Having food in the stomach typically will slow down a medications absorption Decreasing medication absorption: Example: Drugs are absorbed more quickly into the body when the stomach is empty. Having food in the stomach will slow down a medication's absorption.

Absorption Ciprofloxacin and Tetracycline form insoluble complexes with calcium in dairy products or fortified foods; also zinc, calcium, magnesium, zinc or iron supplements; aluminum in antacids Stop unnecessary supplements during drug therapy or give drug 2 hours before or 6 hours after the mineral

Examples: Dietary calcium can bind to the antibiotic tetracycline making it unavailable for absorption Amino acids compete for absorption with levodopa Decreasing medication absorption: Example: Dietary calcium can bind to the antibiotic tetracycline. As a result the body does not absorb the amount of antibiotic intended. Example: Dietary amino acids compete for absorption with levodopa.

Absorption Presence of food enhances the absorption of some medications Bioavailability of Axetil (Ceftin), an antibiotic, is 52% after a meal vs 37% in the fasting state Absorption of the antiretroviral drug saquinavir is increased twofold by food

Adsorption: adhesion to a food or food component High fiber diet may decrease the absorption of tricyclic antidepressants such as amitriptyline (Elavil) Digoxin (Lanoxin) should not be taken with high phytate foods such as wheat bran or oatmeal

GI pH can affect drug absorption Achlorhydria or hypochlorhydria can reduce absorption of ketoconozole and delavirdine Antacid medications can result in reduced acidity in the stomach Taking these meds with orange or cranberry juice can reduce stomach pH and increase absorption

Examples: Acidity of food or beverage consumed with a medication can affect absorption Some medications are better absorbed in an acidic environment Other medications can be damaged by an acid environment, these types of medications are often available in coated forms to resist stomach acidity Decreasing medication absorption: Example: The type of food or beverage consumed with a medication can affect a medication's absorption. Some medications are better absorbed in an acidic environment. Other medications can be damaged by an acid environment, these types of medications are often available in coated forms to resist the stomach acidity.

2. 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

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

3. Food-Drug Interactions: Medication Metabolism
Some foods or nutrients in foods may interfere with a medication’s metabolism or action in the body by: Affecting enzyme systems Interacting with medications Having a similar chemical structure resulting in competition Interfering with medication metabolism: Foods or nutrients may interfere with a drug's metabolism or a drug's action in the body by interfering with enzymes that metabolize medications or acting as a medication antagonist.

Metabolism (biotransformation)
Primarily in the liver; cytochrome P-450 enzyme system facilitates drug metabolism; metabolism generally changes fat soluble compounds to water soluble compounds that can be excreted Foods or dietary supplements that increase or inhibit these enzyme systems can change the rate or extent of drug metabolism

3. Food-Drug Interactions: Medication Metabolism
Examples: Components in grapefruit juice Inactivate enzymes that metabolize many medications which can result in increased medication levels inhibits the intestinal metabolism (cytochrome P-450 3A4 enzyme) of numerous drugs (calcium channel blockers, HMG CoA inhibitors, anti-anxiety agents) enhancing their effects and increasing risk of toxicity; may interfere with the absorption of other drugs Interfering with medication metabolism Example: Components in grapefruit juice and whole grapefruit inactivate enzymes that metabolize many medications. The lack of enzyme action increase medication levels which can lead to overdose effects. Example: Aged and fermented foods contain a chemical called tyramine that interacts with a medication, monoamine oxidase inhibitor. This interaction can result in dangerously high blood pressure. Example: Vitamin K is structurally similar to the anticoagulant warfarin. Vitamin K can decrease the effectiveness of warfarin.

Grapefruit Inhibits Metabolism of Many Drugs
Inactivates metabolizing intestinal enzyme resulting in enhanced activity and possible toxicity Effect persists for 72 hours so it is not helpful to separate the drug and the grapefruit Many hospitals and health care centers have taken grapefruit products off the menu entirely

Food/Nutrient Effects on Drug Action: MAOIs
Aged and fermented foods Contain a chemical called tyramine that interacts with a medication, monoamine oxidase inhibitor, which can result in dangerously high blood pressure Monoamine oxidase inhibitors (MAOI) interact with pressor agents in foods (tyramine, dopamine, histamine) Pressors are generally deaminated rapidly by MAO; MAOIs prevent the breakdown of tyramine and other pressors Significant intake of high-tyramine foods (aged cheeses, cured meats) by pts on MAOIs can precipitate hypertensive crisis

Vitamin K Structurally similar to the anticoagulant warfarin which can decrease the effectiveness of warfarin

Metabolism Changes in diet may alter drug action Theophylline: a high protein, low CHO diet can enhance clearance of this and other drugs

4. Food-Drug Interactions: Medication Removal
Some food or nutrients in foods may interfere with removal of a medication from the body by: Affecting enzymes involved in preparing medications for removal Altering urine pH Interfering with medication removal: Foods or nutrients may interfere with the removal of a medication from the body by affecting liver enzymes involved in preparing medications for removal from the body or altering the acidity of the urine.

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

Food-Drug Interactions: Medication Removal
Examples Liver enzymes prepare medications for removal from the body These enzymes require nutrients to work properly If nutrients are not present the medication may stay active in the body longer than intended Quinidine is excreted more readily in an acidic urine Foods that cause the urine to be more basic, such as sodium bicarbonate, may reduce quinidine excretion Interfering with medication removal: Example: Liver enzymes prepare medications for removal from the body. These enzymes require nutrients to work properly. If the nutrients are not present the medication may stay active in the body longer than it is supposed to. This may cause an overdose effect. Example: Quinidine is excreted more readily in an acidic urine. Foods that cause the urine to be more basic, such as sodium bicarbonate, may reduce quinidine excretion.

Drug Effects on Nutrition: Metabolism
Methotrexate (cancer and rheumatoid arthritis) and pyrimethamine (malaria, toxoplasmosis) are folic acid antagonists May treat with folinic acid (reduced form of folic acid, does not need conversion to active form) or folic acid supplements

Drug Effects on Nutrition: Excretion
Cisplatin causes nephrotoxicity and renal magnesium wasting resulting in acute hypomagnesemia in 90% of patients (also hypocalcemia, hypokalemia, hypophosphatemia) May require intravenous mg supplementation or post-treatment hydration and oral mg supplementation May persist for months or years after therapy is finished Mg Ca K Ph

Pharmacogenomics Genetically determined variations that are revealed solely by the effects of drugs Affect only a subset of people Examples include G6PD enzyme deficiency, warfarin resistance, and slow inactivation of isoniazid (IHN) or phenelzine G6PD (glucose-6-phosphate dehydrogenase) enzyme deficiency: X-chromosome-linked Can lead to neonatal jaundice, hemolytic anemia or acute hemolysis Most common in African, Middle Eastern, and Southeast Asians Also called favism Fava beans or pollen, Vitamin K or Vitamin C can cause 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

Many Medications These are just a few examples to understand how medications and nutrients can interact, this is not indented to be a complete list of possible interactions There are thousands of medications on the market and numerous new medications that come out ever year Many Medications These are just a few examples to understand how medications and nutrients can interact, this is not indented to be a complete list of possible interactions. There are thousands of medications on the market and numerous new medications that come out ever year.

Alcohol Interacts With Medications
Alcohol can adversely affect medications Alcohol can slow down or speed up how the body metabolizes a medication Medication action can be either intensified or reduced In combination with some drugs will produce additive toxicity In some cases, mixing alcohol and medications can be fatal With CNS-suppressant drugs may produce excessive drowsiness, incoordination Acts as gastric irritant; in combination with other irritants such as NSAIDs may increase chance of GI bleed Alcohol Alcohol and medications do not mix well. Alcohol can adversely affect medications. Alcohol can slow down or speed up how the body metabolizes a medication. As a result, medication action can be either intensified or reduced. In some cases, mixing alcohol and medications can be fatal.

Nutrient Supplements Nutrient supplements themselves can result in drug-nutrient interactions In excessive amounts, vitamin and mineral supplements can act like drugs instead of nutrients Nutrients in excessive amounts may: Compete with other nutrients for absorption, transport or metabolism Have a direct overdose effect Nutrient Supplements Nutrient supplements themselves can result in drug-nutrient interactions. In excessive amounts vitamins and minerals act like drugs instead of nutrients. Nutrients in excessive amounts may compete with other nutrients for absorption, transport or metabolism. In excess, nutrients can have a direct overdose effect. Example: Large amounts of zinc can interfere with copper and iron absorption. Similarly, large amounts of iron can interfere with zinc absorption.

Lower The Risk of Drug-Nutrient Interactions
Eat a healthy diet Follow directions on how to take medications Both prescription and over-the-counter Read warning labels Do not share medications How to Lower The Risk Of Drug-Nutrient Interactions Eat a healthy diet using the USDA Daily Food Plan. Follow directions on how to take medication (prescription and over-the-counter). Read warning labels on both prescription and over-the-counter medications. Do not share medications with others or take other peoples medications.

Summary Most drugs have nutritional status side effects.
Always look for therapeutically significant interactions between food and drugs Identify and monitor high risk patients, those on multiple medications and marginal diets

Capecitabine (Xeloda)
Capecitabine is used to treat breast cancer and colon and colorectal cancers. Possible side effects include nausea and vomiting, numbness or tingling in the extremities, increased fatigue, skin irritation and mouth sores.

Effect of food on the pharmacokinetics of capecitabine (Xeloda) and its metabolites following oral administration in cancer patients. Abstract The extent of these changes, however, varied considerably between the various compounds. Cmax and AUC values were decreased after food, and time until the occurrence of Cmax values were increased. In contrast, the apparent elimination half-life was not affected by food intake. The extent of change in Cmax and AUC was highest for capecitabine and decreased with the order of formation of the metabolites. The "before:after food" ratios of the Cmax values were 2.47 for capecitabine, 1.81 for 5'-DFCR, 1.53 for 5'- DFUR, 1.58 for 5-FU, 1.26 for FUH2, and 1.11 for FBAL. The before: after food ratios of the AUC values were 1.51 for capecitabine, 1.26 for 5'-DFCR, 1.15 for 5'-DFUR, 1.13 for 5-FU, 1.07 for FUH2, and 1.04 for FBAL. The results show that food has a profound effect on the AUC of capecitabine, a moderate effect on the AUC of 5'-DFCR, and only a minor influence on the AUC of the other metabolites in plasma. In addition, a profound influence on Cmax of capecitabine and most of its metabolites was found. Detailed information on the relationship between concentration and safety/efficacy is necessary to evaluate the clinical significance of these pharmacokinetic findings. At present, it is recommended that capecitabine be administered with food as this procedure was used in the clinical trials. Abstract Capecitabine (Ro ) is a novel oral fluoropyrimidine carbamate that was rationally designed to generate 5-fluorouracil (5-FU) selectively in tumors. The effect of food on the pharmacokinetics of capecitabine and its metabolites was investigated in 11 patients with advanced colorectal cancer using a two-way cross-over design with randomized sequence. Patients received repeated doses of 666 or 1255 mg/m2 of capecitabine twice daily. On study days 1 and 8, drug was administered following an overnight fast or within 30 min after consumption of a standard breakfast, and serial blood samples were collected. Concentrations of capecitabine and its metabolites [5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), 5-FU, dihydro-5-fluorouracil (FUH2), and alpha-fluoro-beta-alanine (FBAL)] in plasma were determined by high-performance liquid chromatography or liquid chromatography/mass spectroscopy. Intake of food prior to the administration of capecitabine resulted in pharmacokinetic changes of all compounds involved. The extent of these changes, however, varied considerably between the various compounds. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) values were decreased after food, and time until the occurrence of Cmax values were increased. In contrast, the apparent elimination half-life was not affected by food intake. The extent of change in Cmax and AUC was highest for capecitabine and decreased with the order of formation of the metabolites. The "before:after food" ratios of the Cmax values were 2.47 for capecitabine, 1.81 for 5'-DFCR, 1.53 for 5'-DFUR, 1.58 for 5-FU, 1.26 for FUH2, and 1.11 for FBAL. The before: after food ratios of the AUC values were 1.51 for capecitabine, 1.26 for 5'-DFCR, 1.15 for 5'-DFUR, 1.13 for 5-FU, 1.07 for FUH2, and 1.04 for FBAL. The results show that food has a profound effect on the AUC of capecitabine, a moderate effect on the AUC of 5'-DFCR, and only a minor influence on the AUC of the other metabolites in plasma. In addition, a profound influence on Cmax of capecitabine and most of its metabolites was found. Detailed information on the relationship between concentration and safety/efficacy is necessary to evaluate the clinical significance of these pharmacokinetic findings. At present, it is recommended that capecitabine be administered with food as this procedure was used in the clinical trials. XELODA tablets should be swallowed whole with water within 30 minutes after a meal

Imatinib (Gleevec) Imatinib is used to treat chronic myeloid leukemia. The drug may cause weight gain, diarrhea, muscle aches, fatigue, stomach pain and skin rash

Clinical Pharmacokinetics of Imatinib
Abstract Imatinib is a potent and selective inhibitor of the protein tyrosine kinase Bcr-Abl, platelet-derived growth factor receptors (PDGFRα and PDGFRβ) and KIT. Imatinib is approved for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), which have dysregulated activity of an imatinib-sensitive kinase as the underlying pathogenetic feature. Imatinib is approximately 95% bound to human plasma proteins, mainly albumin and α1-acid glycoprotein. The drug is eliminated predominantly via the bile in the form of metabolites, one of which (CGP 74588) shows comparable pharmacological activity to the parent drug. The faecal to urinary excretion ratio is approximately 5:1. Imatinib is metabolised mainly by the cytochrome P450 (CYP) 3A4 or CYP3A5 and can competitively inhibit the metabolism of drugs that are CYP3A4 or CYP3A5 substrates. Interactions may occur between imatinib and inhibitors or inducers of these enzymes, leading to changes in the plasma concentration of imatinib as well as coadministered drugs. Hepatic and renal dysfunction, and the presence of liver metastases, may result in more variable and increased exposure to the drug, although typically not necessitating dosage adjustment. Age (range 18–70 years), race, sex and bodyweight do not appreciably impact the pharmacokinetics of imatinib. September 2005, Volume 44, Issue 9, pp 879–894 Clinical Pharmacokinetics of Imatinib Bin Peng, Peter Lloyd, Horst Schran Review ArticleFirst Online: 30 September 2012 DOI: / Cite this article as:Peng, B., Lloyd, P. & Schran, H. Clin Pharmacokinet (2005) 44: 879. doi: / kViews Abstract Imatinib is a potent and selective inhibitor of the protein tyrosine kinase Bcr-Abl, platelet-derived growth factor receptors (PDGFRα and PDGFRβ) and KIT. Imatinib is approved for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), which have dysregulated activity of an imatinib-sensitive kinase as the underlying pathogenetic feature. Pharmacokinetic studies of imatinib in healthy volunteers and patients with CML, GIST and other cancers show that orally administered imatinib is well absorbed, and has an absolute bioavailability of 98% irrespective of oral dosage form (solution, capsule, tablet) or dosage strength (100mg, 400mg). Food has no relevant impact on the rate or extent of bioavailability. The terminal elimination half-life is approximately 18 hours. Imatinib plasma concentrations predictably increase by 2- to 3-fold when reaching steady state with 400mg once-daily administration, to 2.6 ± 0.8 μg/mL at peak and 1.2 ± 0.8 μg/mL at trough, exceeding the 0.5 μg/mL (1 μmol/L) concentrations needed for tyrosine kinase inhibition in vitro and leading to normalisation of haematological parameters in the large majority of patients with CML irrespective of baseline white blood cell count. Imatinib is approximately 95% bound to human plasma proteins, mainly albumin and α1-acid glycoprotein. The drug is eliminated predominantly via the bile in the form of metabolites, one of which (CGP 74588) shows comparable pharmacological activity to the parent drug. The faecal to urinary excretion ratio is approximately 5:1. Imatinib is metabolised mainly by the cytochrome P450 (CYP) 3A4 or CYP3A5 and can competitively inhibit the metabolism of drugs that are CYP3A4 or CYP3A5 substrates. Interactions may occur between imatinib and inhibitors or inducers of these enzymes, leading to changes in the plasma concentration of imatinib as well as coadministered drugs. Hepatic and renal dysfunction, and the presence of liver metastases, may result in more variable and increased exposure to the drug, although typically not necessitating dosage adjustment. Age (range 18–70 years), race, sex and bodyweight do not appreciably impact the pharmacokinetics of imatinib.

Erlotinib (Tarceva) Erlotinib is used to treat non-small cell lung cancer that has spread to nearby tissues or to other parts of the body in patients who have already been treated with at least one other chemotherapy medication and have not gotten better. Erlotinib is also used in combination with another medication (gemcitabine [Gemzar]) to treat pancreatic cancer that has spread to nearby tissues or to other parts of the body. Erlotinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells.

Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals. Ling J1, Fettner S, Lum BL, Riek M, Rakhit A. Effect of food on Abstract The effects of food on the pharmacokinetics of erlotinib were investigated in two open- label, randomized studies. In a single-dose crossover study (n = 18), 150 mg of erlotinib was administered under either fasting or fed conditions. In the first period, an approximate doubling in the area under the plasma concentration-time curve was evidenced by the geometric mean ratio (GMR) of 2.09 observed under fed conditions; whereas, in the second period there was a decrease, with a GMR of In a multiple- dose parallel study (n = 22), 100 mg of erlotinib was administered daily for 8 days, either 7 days of fasting followed by feeding on day 8, or the reverse sequence. In this study, food resulted in an increase in the plasma concentration-time curve on day 1, with a GMR of (P = 0.015). In contrast, there was only a 37% increase on day 7, with a GMR of 1.34 (P = 0.252). These studies indicate that food can substantially increase plasma exposure to erlotinib. Given the maximum tolerated dose of erlotinib used in clinical practice, we recommend that erlotinib be taken under conditions of fasting. PMID: DOI: /CAD.0b013e3282f2d8e4

Comparison of the pharmacokinetics of erlotinib administered in complete fasting and 2 h after a meal in patients with lung cancer. Cancer Chemother Pharmacol. 2015 Jul;76(1): doi: /s Epub 2015 May 21. Abstract BACKGROUND: The recommended dose of erlotinib is 150 mg daily either 1 h before a meal (complete fasting) or 2 h after a meal (2 h post- meal), because of the food effect. CONCLUSION: The AUC0-24 increased significantly faster (48-53 % greater) in the 2-h post-meal status than in complete fasting status, which suggested that the two gastric emptying states might differ in their absorption. However, there was no clinically significant difference in bioavailability or toxicity between the two clinically used fed conditions at least in 14 days. PMID: DOI: /s Cancer Chemother Pharmacol. 2015 Jul;76(1): doi: /s Epub 2015 May 21. Comparison of the pharmacokinetics of erlotinib administered in complete fasting and 2 h after a meal in patients with lung cancer. Katsuya Y1, Fujiwara Y, Sunami K, Utsumi H, Goto Y, Kanda S, Horinouchi H, Nokihara H, Yamamoto N, Takashima Y, Osawa S, Ohe Y, Tamura T, Hamada A. Author information Abstract BACKGROUND: The recommended dose of erlotinib is 150 mg daily either 1 h before a meal (complete fasting) or 2 h after a meal (2 h post-meal), because of the food effect. METHODS: We conducted a cross-over pharmacokinetic study to compare the fed bioequivalence in the two conditions. RESULTS: Twenty-three patients with non-small cell lung cancer were included in the analysis. AUC0-24 and C max in the 2-h post-meal status were significantly higher than in the complete fasting status (GMR = 1.33, P < 0.001; GMR = 1.44, P < 0.001, respectively). However, because the concentration of erlotinib did not reach the steady state within 7 days in the complete fasting state, we conducted analyses only on day 14, which showed no significant difference in AUC0-24 or C max between the two conditions. The more rapid increase in AUC0-24 and C min did not produce any earlier and more severe toxic events. CONCLUSION: The AUC0-24 increased significantly faster (48-53 % greater) in the 2-h post-meal status than in complete fasting status, which suggested that the two gastric emptying states might differ in their absorption. However, there was no clinically significant difference in bioavailability or toxicity between the two clinically used fed conditions at least in 14 days. PMID: DOI: /s

Vinorelbine (Navelbine)
Vinorelbine is used to treat non-small cell lung cancer and breast cancer. Side effects can include constipation, fatigue and weakness, increased risk of infection and nausea and vomiting.

The effects of food and divided dosing on the bioavailability of oral vinorelbine.
Abstract Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m2 per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22 +/- 28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (Tmax) increased from 1.3 +/- 1.6 h in the fasting state to 2.5 +/- 1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16 +/- 51% when vinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized Cmax and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbine indicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity. PMID: Cancer Chemother Pharmacol. 1996;39(1-2):9-16. The effects of food and divided dosing on the bioavailability of oral vinorelbine. Rowinsky EK1, Lucas VS, Hsieh AL, Wargin WA, Hohneker JA, Lubejko B, Sartorius SE, Donehower RC. Author information Abstract The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors. A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80 mg/m2 per week either in the fasting state or after ingestion of a standard meal. Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m2 per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22 +/- 28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (Tmax) increased from 1.3 +/- 1.6 h in the fasting state to 2.5 +/- 1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16 +/- 51% whenvinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized Cmax and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbineindicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity. PMID:

The effects of food on the pharmacokinetic profile of oral vinorelbine
Abstract. The effects of food on the pharmacokinetics and safety profile of a soft-gel capsule formulation of vinorelbine (Navelbine Oral) were evaluated in fed and fasted patients with solid tumours or lymphomas. A group of 18 patients (12 planned) were entered into a multicentre phase I pharmacokinetic study following a crossover design with a 1-week wash-out period. Patients received the first dose of 80 mg/m2 oral vinorelbine either after fasting or after ingestion of a standard continental breakfast. The second dose of 80 mg/m2 was administered 1 week later in the alternate feeding condition to the first dose. Of the 18 patients, 13 were eligible for pharmacokinetic evaluation. The mean time to maximum concentration (Tmax) was shorter in fasted patients (1.63±0.98 h in blood, 1.67±0.96 h in plasma) than in fed patients (2.48±1.40 h in blood, 2.56±1.65 h in plasma) but these differences are not likely to modify the safety and/or efficacy of oral vinorelbine. Values for Cmax and AUC were similar in fed and fasted patients and no significant differences were observed. The safety profile of oral vinorelbine observed in this limited number of patients appears to be comparable to that usually reported for vinorelbine, the main toxicity being neutropenia. Only one episode of febrile neutropenia was reported. The main nonhaematological toxicities encountered were gastrointestinal, consisting of nausea, vomiting, diarrhoea and constipation. A tendency for a lower incidence of vomiting was suggested when oral vinorelbine was administered after a standard breakfast. Based on this study, the administration of oral vinorelbine to fasted patients is not mandatory since administration after a standard breakfast does not lead to differences in body exposure to the drug. As the comfort of patients may be improved when the treatment is administered after a light meal, this procedure can be recommended in clinical practice. The effects of food on the pharmacokinetic profile of oral vinorelbine Roland Bugat, Philippe Variol, Henri Roché, Pierre Fumoleau, Gilles Robinet, Isabelle Senac Original ArticleReceived: 13 November 2001Accepted: 03 May 2002 DOI: /s x Cite this article as:Bugat, R., Variol, P., Roché, H. et al. Cancer Chemother Pharmacol (2002) 50: 285. doi: /s x19Citations 87Views Abstract. The effects of food on the pharmacokinetics and safety profile of a soft-gel capsule formulation of vinorelbine (Navelbine Oral) were evaluated in fed and fasted patients with solid tumours or lymphomas. A group of 18 patients (12 planned) were entered into a multicentre phase I pharmacokinetic study following a crossover design with a 1-week wash-out period. Patients received the first dose of 80 mg/m2 oral vinorelbine either after fasting or after ingestion of a standard continental breakfast. The second dose of 80 mg/m2 was administered 1 week later in the alternate feeding condition to the first dose. Of the 18 patients, 13 were eligible for pharmacokinetic evaluation. The mean time to maximum concentration (Tmax) was shorter in fasted patients (1.63±0.98 h in blood, 1.67±0.96 h in plasma) than in fed patients (2.48±1.40 h in blood, 2.56±1.65 h in plasma) but these differences are not likely to modify the safety and/or efficacy of oral vinorelbine. Values for Cmax and AUC were similar in fed and fasted patients and no significant differences were observed. The safety profile of oral vinorelbine observed in this limited number of patients appears to be comparable to that usually reported for vinorelbine, the main toxicity being neutropenia. Only one episode of febrile neutropenia was reported. The main nonhaematological toxicities encountered were gastrointestinal, consisting of nausea, vomiting, diarrhoea and constipation. A tendency for a lower incidence of vomiting was suggested when oral vinorelbine was administered after a standard breakfast. Based on this study, the administration of oral vinorelbine to fasted patients is not mandatory since administration after a standard breakfast does not lead to differences in body exposure to the drug. As the comfort of patients may be improved when the treatment is administered after a light meal, this procedure can be recommended in clinical practice.

Oral Cyclophosphamide (Cytoxan)
Cyclophosphamide is used for a wide variety of cancers. These include breast cancer, leukemia, cutaneous T-cell lymphoma, lung cancer, multiple myeloma and ovarian cancer. This drug can cause hair loss, nausea and vomiting, mouth sores and loss of appetite, according to the American Cancer Society.

Cytoxan - Clinical Pharmacology
Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA. Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites, but from 5 to 25% of the dose is excreted in urine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma. Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug is low but some metabolites are bound to an extent greater than 60%. It has not been demonstrated that any single metabolite is responsible for either the therapeutic or toxic effects of cyclophosphamide. Although elevated levels of metabolites of cyclophosphamide have been observed in patients with renal failure, increased clinical toxicity in such patients has not been demonstrated.

Etoposide (Toposar) Etoposide is used to treat prostate cancer, Kaposi's sarcoma, small cell lung cancer and lymphoma. Side effects may include increased risk of infection, hair loss, loss of appetite, nausea and vomiting. Uses Etoposide is used alone or in combination with other medications to treat certain forms of lung cancer (such as small cell lung cancer). Etoposide works by slowing the growth of cancer cells. OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by yourhealth care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional. This medication may also be used for certain types of leukemias and lymphomas,ovarian cancer, testicular cancer, and a certain type of prostate cancer.

The effect of food and concurrent chemotherapy on the bioavailability of oral etoposide.
Abstract There is no information on the effect of food or concurrent drug administration on the bioavailability of oral etoposide, despite the fact that treatment is frequently administered over several days and most often in combination with other cytotoxic agents. The influence of these factors has been studied in 11 patients, receiving combination cytotoxic therapy for extensive small cell lung carcinoma. Neither food nor concurrent oral or intravenous chemotherapy had a significant effect on the mean plasma concentrations of etoposide, achieved following oral administration. Wide variation in peak plasma concentrations and in area under the concentration time curve (AUC) occurred both between and within patients. It appears unnecessary for patients receiving etoposide (at 100 mg) to fast prior to drug administration. Furthermore, oral etoposide (at 100 mg and at 400 mg) may be given in combination with other cytotoxic agents without compromising its bioavailability.

Bioavailability and pharmacology of oral idarubicin.
Idarubicin (Idamycin) This oral chemotherapy drug is used to treat breast cancer and acute nonlymphocytic leukemia. This drug may cause an increased risk of infection, nausea and vomiting, skin rash and hair loss. Interactions with food have not been established.

Drugs known to interact with grapefruit juice
Anti-hypertensives (filodipine, nifedipine, nimodipine, nicardipine, isradipine) Immunosuppressants (cyclosporine, tacrolimus) Antihistamines (astemizole) Protease inhibitors (saquinavir) Lipid-Lowering Drugs (atorvastatin, lovastatin, simvastatin) Anti-anxiety, antidepressants (buspirone, diazepam, midazolam, triazolam, zaleplon, carbamazepine, clomipramine, trazodone

Excretion —Patients on low sodium diets will reabsorb more lithium along with sodium; patients on high sodium diets will excrete more lithium and need higher doses —Urinary pH: some diets, particularly extreme diets, may affect urinary pH, which affects resorption of acidic and basic medications

Food/Nutrient Effects on Drug Action: Caffeine
Increases adverse effects of stimulants such as amphetamines, methylphenidate, theophylline, causing nervousness, tremor, insomnia Counters the antianxiety effect of tranquilizers

Drugs that Affect the GI Tract
Alendronate (Fosamax) anti-osteoporosis drug—patients must sit upright 30 minutes after taking it to avoid esophagitis Aspirin or other NASAIDs –can cause GI bleeding, gastritis Orlistat – blocks fat absorption, can cause oily spotting, fecal urgency, incontinence Narcotic agents cause constipation

Examples of Drug Classes That Cause Diarrhea
Laxatives Antiretrovirals Antibiotics Antineoplastics + liquid medications in elixirs containing sugar alcohols

Drugs That May Lower Glucose Levels
Antidiabetic drugs (acarbose, glimepiride, glipizide, glyburide, insulin, metformin, miglitol, neteglinide, pioglitizone, repaglinide, roiglitizone Drugs that can cause hypoglycemia: ethanol, quinine, disopyramide (antiarrhythmic) and pentamidine isethionate (antiprotozoal)

Drugs That Raise Blood Glucose
Antiretrovirals, protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir) Diuretics, antihypertensives (furosemide, hydrochlorothiazide, indapamide) Hormones (corticosteroids, danazol, estrogen or estrogen/progesterone replacement therapy, megestrol acetate, oral contraceptives) Niacin (antihyperlipidemic) baclofen, caffeine, olanzapine, cyclosporine, interferon alfa-2a

Food-Drug Interactions

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