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Introduction
• Drugs, by definition, are
any chemicals that can
affect living processes.
• Interactions between
Drug and Nutrient Interaction in drugs and food can range
from minor to life-
Degenerative Diseases threatening.
• Toxicity can be related to
alterations in drug levels
Mira M within the body, leading to
14 August 2019 either increased or
decreased efficacy. The terms drug-nutrient interaction and
food-drug interaction often are used
interchangeably

Definition
• include specific
changes to the
activity of a drug
Outline caused by a nutrient
or nutrients, or
• Definition changes to the
• Degenerative diseases kinetics of a nutrient
• Appetite Suppressants Drug-nutrient
• Lipid-lowering agents caused by a drug
• Glucose-lowering
interactions
agents
Lisa L. Deal & DeeAnna Wales Van Reken, 2017

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Definition An interaction is said to take place when the

effects of one drug are changed by the
• a broader term that presence of another drug, food, drink or by
also includes the some environmental chemical agent
effects of a medication
on nutritional status
– Gastro-intestinal effects
Food-drug interactions that reduce the
(eg. dry mouth, efficacy of a drug can result in:
stomatitis)
– Appetite changes • longer or repeated stays in health care
– Metabolic effects facilities,
Food-drug interaction (blood glucose or lipid
abnormalities), or • Therapeutic failure
– Renal or urinary effects • disease progression
(retention, frequency, or • and increased morbidity and mortality
acute renal failure).
Lisa L. Deal & DeeAnna Wales VanReken, 2017

André J. Scheen, 2006; Lisa L. Deal & DeeAnna Wales VanReken, 2017

Bioavailability describes the

fraction of an administered
drug that reaches the
systemic circulation Food-drug
interactions

• The majority of
clinically relevant
food–drug interactions
are caused by food-
induced changes in the pharmacodynamic pharmacokinetic
bioavailability of the interactions interactions
drug
• the bioavailability and
clinical effect of most
drugs are correlated
• the bioavailability is an affect the absorption,
affect the activity at distribution,
important the site of action in metabolism, and
pharmacokinetic effect the body excretion “ADME” of
parameter the drug

Lisa L. Deal & DeeAnna Wales VanReken, 2017 Lisa L. Deal & DeeAnna Wales VanReken, 2017

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Degenerative Diseases
• a type of a medical condition
that causes a tissue or organ to
deteriorate over time.
• There are quite a number of
degenerative diseases and
many of them are associated
with aging,
• or gets worse during the
aging process.

Metabolic disorders: diabetes

mellitus, overweight/obesity, and the
so- called metabolic syndrome
Lisa L. Deal & DeeAnna Wales VanReken, 2017 (including atherogenic
dyslipidaemia)

Polypharmacy

the use of four or more can potentiate the

medications during a risks for food-drug
single time period interactions

Lisa L. Deal & DeeAnna Wales VanReken, 2017

André J. Scheen, 2006

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Obesity is defined as an excess of fat

tissue compared with normal values for
age and gender
Obesity
• obesity

altered pathophysiology of the

obese body

Likely to affect drug

distribution within the tissues
and drug elimination,
whereas absorption does not
seem to be modified

Georges Cheymol, 2000

Factors Likely to Affect Pharmacokinetics in Obese people: the actual bodyweight

the Obese exceeded the IBW >20%
• Obese people
Body have larger the percent- age of
composition
absolute lean fat per kg of total
body masses as bodyweight (TBW)
well as fat masses
than non-obese percentage of lean
individuals of the tissue calculated
same age, gender per kg of total
bodyweight (TBW)
and height.

The dosage of these drugs Accumulation of a drug and its metabolites in

Binding to should be based on the adipose tissue may result in prolonged
plasma
proteins Regional ideal bodyweight (IBW) clearance and increased toxicity.
blood flow
and/or tissue
components e.g. in theory, accumulation of fat-soluble drugs
such as the long-acting benzodiazepines (e.g., diazepam [Valium]) Georges Cheymol, 2000
Georges Cheymol, 2000
is more likely to occur

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Cardiac performance and adipose tissue blood Changes in the concentrations of plasma
flow may be altered in obesity binding proteins
• normal body- weight the blood flow in • can affect the movement
fat is poor and accounts for only 5% of of drugs into tissue
the cardiac output, compared with 73% compartments and
in the viscera and 22% in lean tissue consequently their
• blood flow per gram of fat is therapeutic effect
significantly less in morbidly obese
individuals than in moderately obese or
• drugs primarily bound to
lean individuals
albumin (e.g. phenytoin)
showed no significant
changes in protein
binding in obese patients
the reduction of cardiac ventricular
performance in severely obese patients
showed that impairment is correlated There is some uncertainty about the
with the degree of obesity binding to α1 acid glycoprotein acid
(AAG) in obesity
Georges Cheymol, 2000 Georges Cheymol, 2000

Drugs Used in the Management of

Obesity: Appetite Suppressants Methylxanthines
• The pharmacokinetics of drugs: • ordinarily included in daily diet:
– designed to suppress appetite è cause loss of caffeine, theophylline and
bodyweight theobromine are the main
• e.g. Sibutramine: acting body-weight methylxanthines available from
management agent; natural sources
– acts mainly via its desmethyl metabolites M1 and M2. • used to accelerate energy
– The plasma concentrations and pharmacokinetics expenditure and enhance fat loss in
[peak plasma drug concentration (Cmax), AUC, and obesity
t1⁄2β] of the 2 metabolites in obese and non-obese
individuals were reported to be similar (t1⁄2β was • possible influence of bodyweight
about 17 hours in both groups) after oral reduction on the pharmacokinetics
administration of the drug for 2 weeks, but no detailed of caffeine and theophylline
data have been provided.

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Methylxanthines
• Caffeine and theophylline (typically at
much lower amounts) may be ingested in
coffee, tea, cola beverages and chocolate
(Stavric, 1988a), although tea contains
less caffeine than coffee (Gilbert et al.,
1976).
• Tea and chocolate should account for
most the obromine intake through diet
(Stavric, 1988c).
Pharmacokinetic
• after ingestion or administration, methylxanthines are not
expected to accumulate in organs or tissues and, are
posteriorly metabolized in the liver
• systemic effects of theophylline and theobromine, which
remaining longer in the body, should be expected to be
maintained for a longer period of time
• Caffeine is rapidly and completely absorbed in humans at
the gastrointestinal level, mainly at small intestine, but also
at the stomach (20%)
• Following a 5 mg/kg oral administration, plasma peak
concentration was shown to be attained at 29.8 ± 8.1 min.kg,
with a peak plasma concentration of 10.0 ± 1.0 μg/mL
• Caffeine bioavailability is dependent of the administration
route

The hydroxymethylglutaryl

Lipid lowering agents coenzyme A (HMG CoA)

reductase inhibitors Statins
have plasma lipid • The primary effect: is a specific inhibition of
disturbances cholesterol synthesis in the hepatocytes
èreduction in total and LDL cholesterol
levels
• Adverse effects: associated with drug
interactions because of their use in patients
who are likely to be exposed to
leading to atherogenic
dyslipidemia polypharmacy.
• The cytochome P450 enzyme system plays an
important part in the metabolism of most
statins (except pravastatin)→relevant
abdominal adiposity interactions with other pharmacological
agents.
increased
cardiovascular • Food interaction may also be suspected,
the metabolic syndrome
morbidity and mortality especially an inhibition of metabolism by
and patients with type 2 grapefruit juice, a potent CYP inhibitor
diabetes
Kelly Anne M, 2007

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The hydroxymethylglutaryl The hydroxymethylglutaryl

coenzyme A (HMG CoA)
reductase inhibitors Statins coenzyme A (HMG CoA)
reductase inhibitors Statins

• Have very different chemical and • the bioavailability of pravastatin is

pharmacokinetic properties reduced by 31% when taken with food
• The bioavailability of lovastatin • For atorvastatin and fluvastatin,
increases by 50% when taken bioavailability and lipid-lowering
efficacy are unaffected by food intake
with a regular meal
• Excessive ingestion of grapefruit juice
• However, the ingestion of fibers increases the bioavailability of lovastatin,
or fruit as part of a lipid-lowering atorvastatin and simvastatin by 1400, 200
diet may strikingly reduce the and 1500%, respectively èdrug
absorption of lovastatin and may accumulation and the possible
increase the risk of treatment development of adverse effects èshould
failure be avoided in one time
Kelly Anne M, 2007 Kelly Anne M, 2007

Diabetes mellitus (DM) elevated

fasting plasma
glucose (FPG)
(>126 mg/dL)
• Type 2 diabetes mellitus (T2DM) is a
global pandemic
• a complex chronic illness associated
with a state of high blood glucose
level “hyperglycaemia”
• occurring from deficiencies in 2 h PG during
a 75-g oral
insulin secretion, action, or both. hemoglobin
The clinical
diagnosis glucose
A1C level
• Effect: the chronic metabolic >6.5%
of diabetes tolerance test
imbalance criteria (OGTT) (>200
mg/dL)
– major contributor of non-
communicable diseases
– high risk for long-term macro- and
microvascular complications:
cardiovascular diseases (CVDs),
chronic kidney diseases (CKD) random PG
(>200 mg/dL)
with classic
signs and
symptoms of
hyperglycemia
Arun Chaudhury, et.al, 2017
Arun Chaudhury, et.al, 2017

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Glucose-lowering agents Main hypoglycaemic drugs

• are drugs able to reduce
• Promote insulin release • mostly reduce glucose
blood glucose levels
from the pancreas, absorption at the gut
through different therefore enhancing the level.
mechanisms. hypoglycaemic effect • Metformin, as well as
• a good glycaemic control induced by the glitazones, increase
hormone. glucose utilization and
is for preventing and
insulin sensitivity in
delaying progression of peripheral tissues.
microvascular and DPP-IV inhibitors,
macrovascular sulfonylureas, Metformin and α-
glucosidase
complications in patients meglitinides and
inhibitors
incretin mimetics
with diabetes

Paul Arnouts, et.al, 2013

Main hypoglycaemic drugs

• reduce glucose • block glucose

intake by reabsorption from
increasing satiety renal tubular cells,
and regulating therefore inducing
gastric emptying glucose loss
through the urine.

Amylin SGLT-2
analogues inhibitors

Paul Arnouts, et.al, 2013

Paul Arnouts, et.al, 2013

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Class/Drug: BIGUANIDES Class/Drug: BIGUANIDES

Metformin Metformin
• Metformin, the most widely used biguanide is
recommended as a first-line glucose-lowering Decreases hepatic
agent in almost all current diabetes guidelines. glucose production
increases insulin
• Metformin is cheap, has a well- characterized sensitivity; increases
Mechanism of action
efficacy and safety profile, does not increase the insulin- mediated
risk of hypoglycaemia, has some modest lipid- utilization of glucose in
lowering effects peripheral tissues and
decreases glucose
• does not result in weight gain. intestinal absorption
• the use of metformin is associated with a lower
incidence of macro-vascular complications

Paul Arnouts, et.al, 2013

Class/Drug: BIGUANIDES
Pharmacokinetics
Metformin
• Metformin
Disadvantages/side Biotransformation
effects
Usual Dose
and clearance – hydrophilic drug
• Diarrhoea • 500–1000 mg • Eliminated – the absorption occurs almost exclusively in
• Abdominal pain orally one to three unchanged by the
• Vitamin B12 times daily kidney through the upper gastrointestinal tract
glomerular
deficiency
filtration and – After administration: the maximum peak in
• Lactic acidosis
tubular secretion
(very rare)
and excreted in
plasma concentration (2 μg/mL) is reached
the urine (80%) within 2 hour
• No metabolite
generation – The absolute bioavailability of a 500 mg
dose of metformin is ∼50–60%

Paul Arnouts, et.al, 2013

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Pharmacokinetics
• Metformin
– The bioavailability is reduced by food and
tends to decrease with the increase of the dose
administered, suggesting the existence of a
saturation- or permeability/transit time-limited
absorption mechanism.
– The overall volume of distribution is 3.1 L/kg
– highly distributed in erythrocytes, the blood
mean terminal elimination half-life (t1/2) is
notably higher (17.6 h) than the plasma t1/2
(1.5–4.9 h)
Class/Drug: SULFONYLUREAS
• Bind pancreatic β-cells and stimulate insulin
release independently from blood glucose
concentrations → As a consequence, the
hypoglycaemic efficacy decreases over
time when β-cell function is impaired
• Sulfonylureas are strongly protein-bound
(particularly to albumin) and their
displacement by β-blockers, salicylates and
warfarin can lead to hypoglycaemia
8/14/19
Pharmacokinetics
• Metformin
– The last mechanism (involving the human
organic cation transporter-2) accounts for
most of metformin elimination and explains
the high renal clearance of the drug (∼450
mL/min).
– The elimination half-life ranges from 1.5 to
8.7 h and ∼90% of the dose is excreted in
urine within 12–24 h
Class/Drug: SULFONYLUREAS
• 1st generation: acet-ohexamide,
chlorpropamide, tolazamide and
tolbutamide.
• 2nd generation: gliclazide, glimepiride,
glipizide and glibenclamide (or glyburide).
• the most common side effect
– Hypoglycaemia: long-acting sulfonylureas (such
as chlorpropamide and glyburide), especially
in CKD patients because of the fall in renal
gluconeogenesis and accumulation
– Nausea, skin reactions (including
photosensitivity) and abnormal liver function
tests represent other low-incidence side-effects
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Class/Drug: SULFONYLUREAS Class/Drug: SULFONYLUREAS

Chlorpropamide (1st generation) Chlorpropamide (1st generation)

Stimulates insulin Disadvantages/side

Usual Dose
Biotransformation
secretion from the effects and clearance

pancreas; closes • Hypoglycaemia ( • 250–500 mg orally • Eliminated almost

Mechanism of K- ATP channels
frequent) once daily exclusively by the
• Flushing after kidney and
action on β-cell plasma alcohol ingestion excreted in the
• Hyponatreamia urine as
membranes • Increased
unchanged drug
and hydroxylated
cardiovascular
or hydrolyzed
risk and mortality
metabolites

Paul Arnouts, et.al, 2013 Paul Arnouts, et.al, 2013

Class/Drug: SULFONYLUREAS
Pharmacokinetics Tolbutamide (1st generation)
• The drug interacts with ATP-sensitive potassium-
channel receptors on the pancreatic cell surface, Stimulates
promoting the secretion of insulin pancreatic insulin
• rapidly absorbed in the gastrointestinal tract, secretion from the
reaching the highest circulating levels in 2–4 h Mechanism of pancreas -Closes
• Metabolized in the liver (∼80%), primarily via action K-ATP channels on
CYP2C9 b- cell plasma
• the metabolites are mainly excreted in the urine membranes
• The average biological half-life is 36 h

Paul Arnouts, et.al, 2013 Paul Arnouts, et.al, 2013

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Class/Drug: SULFONYLUREAS
Tolbutamide (1st generation)
Disadvantages/side effects
• Hypoglycaemia • 1000–2000 mg orally one
• Increased cardiovascular
risk and mortality
to two times daily
• Sulphonamide allergy
Class/Drug: SULFONYLUREAS
Glipizide (2nd
Mechanism of
action
Usual Dose
Biotransformation and
clearance
• Liver metabolization to
hydroxymethyltolbutamide
(mildly active) and
carboxytolbutamide
(inactive);
• metabolites are excreted
in urine and faeces
Paul Arnouts, et.al, 2013
generation)
Stimulates insulin
release from
pancreatic β cells
Paul Arnouts, et.al, 2013
8/14/19
Pharmacokinetics
• Rapidly absorbed in the gastrointestinal
tract and detectable levels are present in
the plasma within 20 min after oral
ingestion, with peak levels occurring at 3–4
h.
• The half-life of tolbutamide is 4.5–6.5 h
• The metabolism of tolbutamide is mainly
hepatic via CYP2C9 with the generation of
hydroxymethyltolbutamide (mildly active)
and carboxytolbutamide (inactive)
• excreted in urine (75–85%, primarily as
metabolites) and faeces (15–25%)
Paul Arnouts, et.al, 2013
Class/Drug: SULFONYLUREAS
Glipizide (2nd generation)
Disadvantages/side Biotransformation
Usual Dose
effects and clearance
• Hypoglycaemia • 2.5–10 mg daily • Primarily
• Gastrointestinal eliminated by
disturbance hepatic
transformation into
inactive
metabolites;
• 80% excreted in
urine, 10%
excreted in faeces
and 10% excreted
unchanged
Paul Arnouts, et.al, 2013
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Class/Drug: α-GLUCOSIDASE INHIBITORS

Pharmacokinetics Acarbose
• Peak plasma concentrations occur 1–3 h after a
single oral dose
• elimination half-life ranges from 2 to 4 h in
normal subjects, whether given intravenously or Mechanism of action Blocks the action of the
orally α- glucosidase with
reduced hydrolysis of
• metabolized primarily by hepatic transformation complex saccharides.
into several inactive metabolites by aromatic
hydroxylation
• 10% of a dose is excreted as unchanged in urine
and faeces, while ∼90% is found as
biotransformation products in urine (80%) and
faeces (10%)

Paul Arnouts, et.al, 2013 Paul Arnouts, et.al, 2013

Class/Drug: α-GLUCOSIDASE INHIBITORS

Acarbose Pharmacokinetics
• Metabolism by intestinal bacteria and enzymatic
hydrolysis produce over 13 metabolites, at least
Disadvantages/side
Usual Dose
Biotransformation one of which has some biological activity.
effects and clearance
• Only a small amount of the drug (∼34% of the
• Flatulence • 75–300 mg/day • Intestinal dose) is absorbed and the bioavailability is very
• Diarrhoea production of
several low
metabolites, • The peak plasma concentrations are achieved
• some of which ∼1 h after administration.
biologically active.
Intact acarbose • Intact acarbose is almost completely excreted
excreted by the by the kidney with an elimination half-life of ∼2
kidney
h. Less than 2% of the starting dose is recovered
in the urine as an active drug (intact compound
and active metabolite)
Paul Arnouts, et.al, 2013 Paul Arnouts, et.al, 2013

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References
• Kelly Anne Meckling, 2007. Nutrient drug
interactions. CRC Press.
• Lisa L. Deal, Dee Anna Wales, 2017. Clinical: Food-
Drug Interactions. Krause’s food & the nutrition care
process. 14th edition. St. Louis, Missouri
• Georges Cheymol, 2000. Effects of Obesity on
Pharmacokinetics Implications for Drug Therapy.
Clin Pharmacokinet 2000 Sep; 39 (3): 215-231.
• Paul Arnouts, 2013. Glucose-lowering drugs in
patients with chronic kidney disease: a narrative
review on pharmacokinetic properties. Nephrol
Dial Transplant (2014) 29: 1284–1300.

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