13. Diet-treatment interactions

Effect of food on drugs

• more acute

• shows up as an increase or reduction of known effects and side effects of the drug

• often recognized because they are fast acting and tied to an obvious drug response

Effec of drugs on food

• Much slower

• Outcome is related to nutrients/nutrition

• often missed

Nutrition and pharmacology overview

• most of nutrition and supplement have an effect on ADME

Interactions prior to administration

• = mixing drug in food (e.g. patient has trouble swallowing so drug is mixed with apple sauce)

• can be okay, but don’t do it if possible because:

  • dosage forms often need to stay intact

  • medication can degrade or react with the food

• Never mix medicines with food unless you checked.

Main causes of food → drug interactions

• Interactions prior to administration

• Interations in the gastro-intestinal tract

• Interference of uptake from the GI tract

• Modulation of drug biotransformation

• … (other pharmokinetic effects)

• Pharmacodynamic interactions

How can ADME and food be related

• Antibiotics may bind to Ca, Mg, Fe in the gatrointestinal tract because that may form insoluble complex (-)

• Full stomach - empty stomach effects (±)

• Effects of fatty meals (±)

• Interactions during absorption from the intestine (±)

• Effects on metabolism (biotransformation) in the liver (±)

Processes determining oral bioavailability

• Humans are actually not made to take drugs orally

• Because they will pass through liver which is made for detoxification = drug does not work.

• But it should be able to pass through liver and end up in systemic circulation

Taking a drug on a full or empty stomach?

• Delayed gastric emptying → decreased absorption rate

  • If you take a drug on a full stomach the effect takes much longer to take place

  • If you take a drug on an empty stomach the effect takes place immediately

• Effect on bio-availability depends on:

  • Acid stability

  • dissolution behavior in stomach

Effects of taking a drug after consuming a fatty meal

• Increased bioavailability of lipophilic durgs:

  • For lipophilic drugs - such as Abiraterone, Lapatinib and cannabidiol (CBD) - taking these with a fatty meal increases its systemic absorption greatly.

• Delayed gastric emptying: High fat meals take much longer to digest, this may cause drugs to take effect much later.

• Unpredictable fluctuations and risk of toxicity: although high absorption seems advantageous, meal fat content may vary widely from day to day. Therefore medications with a narrow therapeutic window - such as oral chemotherapies, unpredictable spikes are not great.

• Therefore during chemotherapy they attempt to have a very stable diet to avoid sudden dietary changes

Explain this scheme

• Summarizes how a high-fat meal affects oral drug absorption

• Depending on where a drug falls in the biopharmaceutics classification system which sorts drugs along two axes: solubility and pemeability

• F= bioavailability

• Tmax = time to reach max plasma concentration

• Class 1 = like paracetamol

• Class 2 = typically compounds not well soluble in water. Therefore if they are highly permeable, then they are likely fat soluble.

• Class 3 = Usually very polar compounds, so polar that therefore they do not pass membrane and can be used if there is an infection in the stomach. Polarity causes them to be taken up much slower.

• Class 4 = most chemotherapeutic drugs. Hard to predict, can go any direction.

Why it is so difficult to predict what certain drugs will do?

• Humans evolved active transport mechanisms in the gut and liver to absorb essential nutrients (vitamins, amino acids, cholesterol) while activley pumping out plant toxins

• However, many drugs use these nutrients transporters, cellular pumps, and liver detoxification enzymes to enter the bloodstream or be expelled

• Because foods, dietary supplements, herbal compounds, and drugs all compete for the same specific transport and metabolic pathways, interferences are highly unpredictable. A specific plant compound might block or stimulate a transporter used by one drug while leaving another drug untouched—even within the same class of medication

• Many targeted therapies against cancer have complicated physical properties. Because these drugs have a narrow therapeutic window, subtle variations in how our evolved transport systems handle them can easily cause unexpected drug toxicity or treatment failure.

Important enzyme present in the liver

• Cytochrome P450

• Involved in the metabolism of many drugs

• There are different forms in the liver (and intestines), each with a certain selectivity for certain substances (different forms seen in picture)

• Activity may differ per person (age, gender, polymorphism) and per situation

• Affected by other pharmaceuticals and sometimes also food.

CYP3A4

• An isoform of CYP450

• Commonly used enzyme in regards to drugs.

• Works in two ways depending if they drug is in an active form or as an inactive pro-drug

  • If an active drug is broken down into an inactive form, inhibiting the enzyme increases drug blood levels whereas stimulating it lowers drug levels

  • If a pro-drug requires CYP3A4 to convert into its active metabolite, inhibiting the enzyme prevents the drug from becoming active

    • Grapefruit juice can inhibit CYP3A4 = dangerous

Grapefruit juice, CYP3A4 and drug interactions

• Grapefruit contains flavonoid compounds that inhibit CYP3A4.

• This blocks the breakdown of active drugs, causing plasma concentrations and exposure to rise sharply.

Interactions with St. John’s Wort

• Doesnt inhibit CYP3A4 but stimulates it.

• This accelerates the breakdown of medications such as busulfan, cyclophosphamide, and paclitaxel into inactive forms, leading to abnormally low blood levels and therapeutic failure

Challenges of making drugs against cancer

• Pharmokinetics has often become the final concern

• Frequently poorly soluble in both water and fat (‘brick dust’)

• Low bioavailability

• Many interactions, including with food.

How can high-dose herbal supplements interfere with drug biotransformation? (Curcuma)

• Curcumin acts as an inhibitor of the CYP3A4 enzyme

• For example tamoxifen is used as an anti-hormone drug in breast cancer

• Tamoxifen is only active when converted by CYP2D6 and CYP3A4 into endoxifen

• Therefore high doses of curcuma will reduce the drug efficacy.

• Especially if patients are rapid metabolizers for CYP2D6, if then CYP3A4 is slow due to the curcuma, it will limit the effectiveness of the drug (polymorphism)

Effect of drugs on food

• Effects of drugs in the oral cavity

• Effects on taste or sense of smell

• Effects on appetite or satiety (+ or -)

• Various effects in the GI tract

• Metabolic effect

• Disturbance of absorption or metabolism of micronutrients

• Disturbance of microbiota

Nutrition related problems caused by drugs

• Direct GI effects: loss of appetite, nausea, vomiting, and altered taste, mucositis, xerostomia, diarrhea, constipation

• Protein-energy malnutrition/weight loss (because you eat less if nauseaus, altered taste, etc)

• Specific nutrient deficiencies, such as B12 and folic acid depletion from antifolate drugs, electrolyte imbalances

Side effects of drugs in the oral cavity

• Diverse forms of ulcera, opportunistic infections

• Erythema, swelling of gingiva, salivary glands

• Tongue abnormalities

• Problems with (false-) teeth

• taste and/or smell disorders

• dry mouth

Xerostomia

• Common in cancer patients

• Often associated with/caused by drug use

• long list of compounds potentially involved, in particular: many anti-cancer drugs, also other tricyclic anti-depressants, SSRIs, anti-cholinergics, beta-blockers, opiates, some antihistamines etc.

Cachexia

a complex condition marked by severe, unintentional weight loss and muscle wasting that cannot be reversed by normal nutrition alone

• Changes drug adminstration as ADME is changed

• e.g. if drug is lipophilic normally a higher dose would be given as some would end up in people’s fat

• Therefore people with cachexia need a lower dose