pharmacokinetic drug interaction and induction and inhibition of drug metabolism

Presented by:
SUJITHA MARY
M.PHARM
SECOND SEMESTER

DRUG INTERACTION
 Drug interaction are said to occur when the pharmacological
activity of a drug is altered by the concomitant use of another
drug or by the presence of food, drink or environmental
chemicals.
 Object drug: the drug whose activity is affected by such an
interaction
 Precipitant drug: the agent which precipitates such an
interaction

PHARMACOKINETIC INTERACTION
 These interactions are those in which the ADME of the
object drug are altered by the precipitant drug .
 The resultant effect alter the plasma concentration of the
object drug
CLASSIFICATION
i. Absorption interaction
ii. Distribution interaction
iii. Metabolism interaction
iv. Excretion interaction

Absorption interaction
May result in a change in the rate of absorption and a change in the
amount of drug absorbed.
Absorption after oral administration is common
A decrease in rate of absorption is clinically significant in acute
conditions such as pain than for drugs used in chronic therapy
Ateration in parenteral drugs are rare

Object drug Precipitant drug Influence on object
drug
Tetracycline ,
ciprofloxacine,
penicillamine
Antacids, food and
mineral supplements
containing Al, Mg, Fe,
Zn, Bi, Ca ions
Formation of poorly
soluble and
unabsorbable complex
with such heavy
metals
Cephalexin , warfarin,
tyroxine
cholestyramine Reduced absorption
due to adsorption and
binding
1 . Complexation and adsorption
MECHANISMS

2. Alteration of GI pH
drug
Sulphonamides,
aspirin
antacids Enhanced dissolution
and absorption rate
Ferrous sulphate Sodium
bicarbonate,
calcium carbonate
Decreased dissolution
and absorption
Ketoconazole,
tetracycline,
atenolol
antacids Decreased dissolution
and bioavailability

3 . Alteration of gut motility/Rate of gastric
emptying
drug
Aspirin, diazepam,
levodopa,
paracetamol
metoclopramide Rapid gastric
emptying, increased
rate of absorption
Levodopa, lithium
carbonate,
mexiletine
Anticholinergics
(atropine)
Delayed gastric
emptying, decreased
rate of absorption

3 . Alteration of gut motility/Rate of gastric emptying
drug
Aspirin, diazepam,
levodopa,
paracetamol
metoclopramide Rapid gastric
emptying, increased
rate of absorption
Levodopa, lithium
carbonate,
mexiletine
Anticholinergics
(atropine)
Delayed gastric
emptying, decreased
rate of absorption

4 . Alteration of GI microflora
drug
Digoxin Tetracycline,
erythromycin
Increased
bioavailability due
to destruction of
bacterial flora that
inactivates digoxin
in lower intestine
oral contraceptives ampicillin Decreased
reabsorption of
drugs secreted as
conjugates via bile
intestine

5 . Mal absorption syndrome
Object drug Precipitant drug Influence on
object drug
Vitamin A, B12,
digoxin
Neomycin,
colchicine
Inhibition of
absorption due to
malabsorption or
steatorrhoea

Distribution interaction
 Distribution pattern of the object drug is altered
 Competitive displacement interactions are the
clinically significant interactions
 It occurs when two drugs are capable of binding to the
same site on the protein
 Greater risk interactions occur when the displaced
drugs are highly protein bound, has small Vd , narrow
therapeutic index & displacer drugs has higher degree
of affinity than the drug to be displaced

Object drug
(displaced drug)
Precipitant drug
(displacer)
Influence on object
drug
Warfarin Phenylbutazone,
chloral hydrate,
salicylate
Increased clotting
time,increased risk of
haemorrhage
Tolbutamide Sulphonamide Increased
hypoglyceamic effect
methotrexate Sulphonamide,
salicylic acid
Increased methotrexate
toxicity
phenytoin Valproic acid Phenytoin toxicity

Metabolism interaction
 Metabolism of the object drug is altered
 Most important
 common cause of pharmacokinetic interactions
 Mechanisms involved:
1. Enzyme induction: increased rate of metabolism
 It reduce the blood level & clinical efficacy of co-
administered drugs
 Enhance the toxicity of drugs having active metabolites
 Usually not hazardous
2. Enzyme inhibition: decreased rate of metabolism
 Most significant
 Accumulation of drugs to toxic levels
 Can be fatal

1 . Enzyme induction
Object drug Precipitant
drug
Influence on object
drug
Corticosteroids, oral
contraceptives,
phenytoin, TCA
barbiturates Decreased plasma
levels, decreased
efficacy of object drugs
Corticosteroids, oral
contraceptives,
theophylline,
cyclosporin
phenytoin
Oral contraceptives, oral
hypoglycaemics,
coumarin
rifampicin

2 . Enzyme inhibition
Object drug Precipitant
drug
Influence on object drug
Thymine rich
foods(cheese,
liver, yeast
products)
Phenelzine,
pargyline
Enhanced absorption of
unmetabolised tymine, increased
pressor activity, potentially fatal risk
of hypertensive crisis
Propranolol,
CCB
Grapefruit juice Enhanced absorption of drugs,
increase the risk of toxicity
TCA Chlorpromazine,
haloperidol
Increased plasma half life of
tricyclic's, increased risk of sudden
death from cardiac disease in such
patients

Excretion interaction
 Excretion pattern of object drug is altered
 Clinically significant interactions occur when appreciable
amount of drug or its metabolites are eliminated in the urine
 Excretion pattern are affected by alteration in:
 GFR
 Renal blood flow
 Passive tubular reabsorption
 Active tubular secretion
 Urine pH
Major mechanisms involved:
 Alteration in renal blood flow
 Alteration of urine pH
 Competition for active secretion
 Forced diuresis
Biliary excretion is another major mechanism

1 . Change in active tubular secretion
drug
Penicillin,
cephalosporin,
nalidixic acid, PAS,
methotrexate,
dapsone
Probenecid Elevated plasma
levels of acidic
drugs, risk of toxic
reactions
Procainamide Cimetidine Increased plasma
levels of basic object
drugs, risk of toxicity
Acetohexamide Phenylbutazone Increased
hypoglycaemic effect

2 . Changes in urine pH
object drug
Amphetamine,
tetracycline,
quinidine
Antacids,
thiazides,
acetazolamide
Increased passive
reabsorption of
basic drugs,
increased risk of
toxicity

3 . Changes in renal blood flow
object drug
Lithium
bicarbonate
NSAIDs
(inhibitors of
prostaglandin
synthesis)
Decreased renal
clearance of
lithium, risk of
toxicity

PRINCIPLES OF DRUG
INTERACTION MANAGEMENT
The consequences of drug interactions may be:
 MAJOR: Life threatening
 MODERATE: Deterioration of patient’s Status
 MINOR : Little effect

GUIDELINES TO MANAGE DRUG INTERACTIONS
 Identify Patient Risk Factors Such As Age, Nature Of Medical
Condition, Dietary Habits , social Status, Etc
 Take Thorough Drug History And Maintain Complete Patient
Medication Records
 Keep Knowledge About Actions Of Drug Being Utilized
 Consider Therapeutic Alternatives
 Avoid Complex Drug Regimen Wherever Possible
 Educate The Patient To Comply With Instructions For Administering
Medications
 Monitor Therapy: Any Change In Patient Behaviour Should Be
Suspected As Drug Related Until That Possibility Is Excluded
 Individualize Therapy: priority Should Be Designed To The Needs &
Clinical Response Of The Individual Patient, Rather Than To The
Usual Dosage Recommendations, Standard Treatment & Monitoring
Guidelines
 Involve The Patient As A Partner In Health Care. If The Optimal
Benefits Of Therapy Are To Be Achieved With Minimal Risk, Each
Participiant Must Be Knowledgeable About & Diligent In Fulfilling His
Responsibilities

INTRODUCTION
•Metabolism based drug interactions can have a
significant influence on the use and safety of many
drugs.
•Induction of drug metabolism can lead to increased
metabolism , reduced pharmacological action and short
duration of action of drug being metabolised.
•The major organ involved in metabolism is liver and
enzyme is CYP-450.
•Induction CYP-450 enzyme in the liver is responsible
for induction of metabolism.

INDUCTION OF DRUG METABOLISM
The phenomenon of increased drug metabolizing ability of the
enzymes by several drug and chemicals – enzyme induction.
A number of drugs can cause an increased liver enzyme activity
. This in turn can increase the metabolic rate of the same or
other drugs.
Dosing rate may need to be increased to maintain effective
plasma concentrations.
Eg:-Phenobarbitone will induce the metabolism of
itself,phenytoin, warfarin etc.

 Rifampicin has been shown to cause up to a twenty times
increase in midazolam metabolism.
 Cigarette smoking can cause increased metabolism of
theophylline (two fold increase ) and other compounds.
AUTO-INDUCTION: drugs that can stimulate its own
metabolism
Eg; Carbamazepine

PROPERTIES OF ENZYME INDUCERS
1. Lipophilic compounds
2. Substrates of induced enzyme system
3. They have long elimination half life.
MECHANISMS INVOLVED IN ENZYME INDUCTION
1. Increase in liver size and liver blood flow
2. Increased microsomal protein content
3. Increased stability of enzymes
4. Increased synthesis of CYP450 enzymes
5. Decreased degradation of CYP450 enzymes
6. Proliferation of smooth endoplasmic reticulum

1.Phenobarbitone induced accelerated metabolism
 Phenobarbitone induces the metabolism of many drugs, thus
affecting the intensity and duration of the pharmacological
action.
Eg; Oral anticoagulants, tricyclic anti-depressants,
corticosteroids, Theophylline, muscle relaxant
- Therapeutic efficacy of these drugs is reduced.
A. WARFARIN - PHENOBARBITAL
Phenobarbital increases the metabolism of warfarin and
decreases anticoagulant action lead to increased risk of
thrombus formation.
To compensate this dose of warfarin should be increased until
desired effect is obtained.

B. ORAL CONTRACEPTIVES
Phenobarbital , rifampicin, can increase the
metabolism of steroid hormones (estrogen,
progestins) used in oral contraceptives.
This leads to reduced effectiveness

2.Rifampicin
 One of the potent enzyme inducing agent is the
antituberculous agent rifampicin.
 Mechanism involved:Proliferation of smooth
endoplasmic reticulum
The increase was noted after two days and reached a
maximum by five days.
 The cytochrome P-450 content of human liver has also
been shown to increases
 autoinduction

3. Cigarette smoking
 Increases the metabolism of many drugs and
chemicals.
 Eg: The lower plasma concentrations of phenacetin in
smokers.
 Increased metabolism of diazepam, theophylline.
 Hepatic drug metabolism as assessed by antipyrine
clearance may be increased by 30% in heavy smokers
 Polycyclic aromatic hydrocarbons (PAH) are a
prominent component of cigarette smoke and are
known inducers of hepatic metabolism.

Consequences of enzyme induction includes:
 Decrease in pharmacological activity of drugs. .
 Increase in activity where the metabolites are active.
 Altered physiological status due to enhanced metabolism
of endogenous compounds such as sex hormones.

INDUCERS DRUGS WITH ENHANCED
METABOLISM
BARBITURATES Coumarins, phenytoin, cortisol, testosterone, oral
pills
ALCOHOL Phenobarbital, coumarins, phenytoin
PHENYTOIN Cortisol,coumarins, oral pills, tolbutamide
RIFAMPICIN Coumarins, oral pills, tolbutamide, rifampicin
CIGERRETTE SMOKE Nicotine, amino azo-dyes

INHIBITION
 The phenomenon of decreased drug metabolizing ability
of the enzymes by several drugs and chemicals is called as
enzyme inhibition.
 If a drug inhibit metabolism of other drug – results in
prolonged and intensified action of other.
eg; Grapefruit juice and ketoconazole can inhibit the elimination
of the HMG-CoA reductase inhibitors lovastatin and simvastatin.
After oral dosing, these drugs are normally extracted rapidly by
the liver (first-pass effect). Therefore, their bioavailability can be
greatly amplified

 The process of inhibition may be of two types:
[1] Direct inhibition.
[2]Indirect Inhibition
1.Direct Inhibition;-
 It may result from the interaction at enzyme site, the
outcome being a change in enzyme activity.
 can occur by one of the three mechanisms:
a)competitive
b)Non-competitive
C)product

a) Competitive inhibition:
This occurs when ‘normal’ substrate and the inhibitor
substrate share the structural similarities. Many enzymes
have multiple drug substrates that can compete with each
other.
Eg: Methacholine inhibits metabolism of Ach by competing
with it for cholinesterase.
b)Non-competitive inhibition:
 It arises when structurally un-related agent interacts with
the enzyme and prevents the metabolism of drugs.
 Eg: Isoniazid inhibits the metabolism of Phenytoin .

c)Product Inhibition:
 This occurs when metabolic product generated by the
enzyme inhibits the reaction on the substrate (feedback
inhibition).
 This usually occurs when the metabolic product has physical
characteristics very similar to that of substrate.
 Eg: Xanthine Oxidase inhibitors (Allopurinol) and MAO
inhibitors (Phenelzine) inhibits the enzyme activity directly.

2)Indirect Inhibition;-
It is brought about by one of the two mechanisms:
a)Repression
b)Altered physiology
a)Repression:
 it is defined as the decrease in enzyme content.
 It may be due to fall in the rate of enzyme synthesis. Eg;
ethionine, puromycin and actinomycin-D
 or because of rise in the rate of enzyme degradation such as
by Carbon tetrachloride, Carbon disulphide, Disulfram etc.

b)Altered Physiology:
 due to nutritional deficiency or hormonal
imbalance,pregnancy,disease condition etc.
 Enzyme inhibition is more important clinically than enzyme
induction, especially for drugs with narrow therapeutic
index.
 Eg: anticoagulants, antiepileptics, hypoglycemics, results in
prolonged pharmacological action with increased possibility
of precipitation of toxic effects.

INHIBITORS DRUGS WITH DECREASED
METABOLISM
MAO inhibitors Barbiturates, tyramine.
Coumarins Phenytoin
allopurinol 6-mercaptopurine
PAS Phenytoin,hexobarbital.
Fluoxetine,
fluoxamine,ketoconazole
Omeprazole, pantoprazole,rabeprazole
Amiodarone, bupropion,
Chlorpheniramine,
cimetidine
haloperidol
risperidone
thioridazine

 A number of compounds are taken up into the liver
by carrier-mediated systems, while more lipophilic
drugs pass through the hepatocyte membrane by
diffusion.
• Most water soluble drugs and metabolites with
high molecular weight(>450) are excreted in the
bile.

 three groups of compounds enter the bile.
 Group A: compounds whose concentration in bile and
plasma are almost identical (bile–plasma ratio of 1). Eg:-
glucose, ions such as Na, K, and Cl.
 Group B: Compounds whose ratio of bile to blood is much
greater than 1, usually 10 to 1,000.
Eg:- bile salts, bilirubin, glucuronide
 Group C : compounds for which the ratio of bile to blood is
less than 1, Eg:- inulin, sucrose, and proteins.

 Only small amounts of most drugs reach the bile
by diffusion.
 Biliary excretion plays a major role (5–95% of the
administered dose) in removal for some anions,
cations, and certain un-ionized molecules, such as
cardiac glycosides.
 Cardiac glycosides, anions, and cations are
transported from the liver into the bile by carrier-
mediated active transport systems.

Inhibition of biliary excretion
Hepatobiliary drug interaction:
 Most water soluble drugs and metabolites with
high molecular weight(>450) are excreted in the
bile.
 Excretion is mainly through transporters.
 Co- administration of drugs which inhibits the
co transporter involved in biliary excretion can
reduce the excretion of drug which are
substrates of the transporter, leading to
elevated plasma drug concentration.
 Drug interaction in biliary excretion affect the
residence time and AUC of unchanged drug in
plasma

 P- glycoprotein is an ATP dependent drug efflux pump,
responsible for decreased drug accumulation in cells
 .
 Biliary and urinary excretion of digoxin, mediated by p-
gp are inhibited by quinidine which is an inhibitor of p-gp
 Patients receiving combination leads to elevated plasma
digoxin concentration and digoxin induced toxicity.
Transporte
r
Drug Inhibitor Result of interaction
P- gp Digoxin Quinidine Decrease in biliary excretion

 Verapamil and cyclosporine are both inhibitors of p-gp,
verapamil is a substrate for p-gp and is a competitive
inhibitor of this pump, where as cyclosporine inhibit
transport function by interfering with substrate recognition
and ATP hydrolysis
 Decreased clearance of drug through inhibition of p-gp
leads to increased AUC and increased toxicity
 Examples:-
 Decreased vincristine clearance in presence of verapamil
 Decreased etoposide or doxorubicin clearance in presence of
cyclosporine

FACTORS AFFECTING INDUCTION
& INHIBITION OF DRUG
METABOLISM

• Eg: organophosphate insecticides
• Heavy metals-mercury, arsenic
ENVIRONMENTAL
CHEMICALS
• Men have more metabolizing capacity
SEX
• Neonates & Infants: slow metabolism
• Children & adults: max. metabolism
• Geriatrics: lower than adults
AGE
• Metabolizing activity is max. From 6 AM – 9AM
• Mini. From 2-5 PM
• Eg; aminopyrine, hexobarbital
CIRCARDIAN RHYTHM
• Pregnancy
• Hormonal imbalance
• Disease states- hepatitis, jaundice
ALTERED PHYSIOLOGICAL
FACTORS
• HIGH PROTEIN- MAX. METABOLISM
• DEFICIENCY OF VITAMINS(A,C,E), MINERALS(Fe, Ca)
• ALCOHOL
DIET

APPLICATIONS
 Helps in drug development
 Role of receptors can be studied by understanding the
molecular mechanism of induction of drug
metabolizing enzymes.
 The different responses of a receptor to the action of a
drug can be studied where the inhibition takesplace.
 Role of receptors can be studied by understanding the
molecular mechanism of induction of drug
metabolising enzymes.

REFERENCES
1. Shargel, L and Yu. Applied biopharmaceutics and
pharmacokinetics: 4th edition.
2. Clinical Pharmacokinetics by Rowland & Tozer
3. Basic pharmacokinetics Dr Sunil S Jambhekar and Dr
Philip J Breen, page no:328

pharmacokinetic drug interaction and induction and inhibition of drug metabolism

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