DRUG DISTRIBUTION

DRUG DISTRIBUTION
Once a drug enters into the blood stream, the drug is
subjected to a number of processes known as
Disposition Processes that tend to lower the plasma
concentration of the drug.

1. Distribution which involves reversible transfer of

a drug between compartments.

2. Elimination which involves irreversible loss of

drug from the body. It comprises of
biotransformation and excretion.
DRUG DISTRIBUTION
CONTENTS
 Definition
 Factors Affecting Drug Distribution
a) Tissue Permeability of the Drug
b) Organ/tissue Size and Perfusion Rate
c) Binding of Drugs to Tissue Components
d) Miscellaneous
 Volume of Distribution
– Significance
 One Compartment Open Model
 Non Compartment Method
 References
DRUG DISTRIBUTION
DEFINITION

 Drug Distribution is defined as the Reversible

transfer of drug between one compartment
(blood) to another (extra vascular tissue).
DRUG DISTRIBUTION
Significance :- Pharmacological action of drug
depends upon its concentration at the site of action.

Thus, distribution plays important role in

 Onset of Action
 Intensity of Action
 Duration of Action
DRUG DISTRIBUTION
STEPS IN DRUG DISTRIBUTION
 Permeation of Free Drug through capillary wall
& entry in to ECF.
 Permeation of drugs from ECF to ICF through
membrane of tissue cell.

Rate Limiting Steps

 Rate of Perfusion to the ECF
 Membrane Permeability of the Drug
► Distribution is a Passive Process, for which the
Driving Force is the Conc. Gradient between the
Blood and Extravascular Tissues

► The Process occurs by the Diffusion of Free

Drug until equilibrium is established
DISTRIBUTION OF DRUG IS NOT UNIFORM
THROUGH OUT THE BODY----WHY ?
 Because tissues receive the drug from plasma
at different rates & different extents.
Organ perfused Blood flow Organ mass Normalized blood
(mL/min) (kg) flow (mL/min/kg)
Liver 1700 2.5 680
Kidney 1000 0.3 3333
CNS 800 1.3 615
Myocardium 250 0.3 833
Fat 250 10 25
Other (muscle) 1400 55.6 25
Total 5400 70
FACTORS AFFECTING DISTRIBUTION OF DRUGS
1. Tissue Permeability of Drugs
 Physicochemical Properties of drug like Mol.
size, pKa, O/W Partition Coefficient
 Physiological barriers to diffusion of drugs

2. Organ/tissue size and perfusion rate

3. Binding of drugs to tissue components.

 Binding of drug to blood components
 Binding of drug to extra cellular components

4. Miscellaneous
1.TISSUE PERMEABILITY OF DRUGS
A. Physicochemical Properties of drugs of the drug
 Molecular size
 pKa
 o/w Partition Co Efficient
B. Physiological barriers to Diffusion of Drugs
 Simple Capillary Endothelial Barrier
 Simple Cell Membrane Barrier
 Blood Brain Barrier
 Blood – CSF Barrier
 Blood Placental Barrier
 Blood Testis Barrier
1.TISSUE PERMEABILITY OF DRUGS
A. Physicochemical Properties of drugs of the drug
1) Molecular size
 Molecular Weight less than 500 to 600 Dalton
easily pass capillary membrane to extracellular
fluid.
 Penetration of drug from ECF to cells is function of
molecular size, ionization constant & lipophilicity
of drug
 From ECF to cross cell membrane through
aqueous filled channels needs particle size less
than 50 Dalton (small) with hydrophilic property
 Large molecular size is restricted or require
specialized transport system
1.TISSUE PERMEABILITY OF DRUGS
A. Physicochemical Properties of drugs of the drug
2) Degree of ionization (pKa)
 The pH at which half of a drug is unionized is called pKa
 A weak acid becomes unionized in a strong acidic environment.
 A weak acid becomes ionized in a neutral or basic environment.
&
 A weak base becomes unionized in a strong basic environment.
 A weak base becomes ionized in a neutral or acidic
environment.
BUT
 The pH of blood plasma, ECF and CSF is 7.4 (constant); except
in acidosis and alkalosis
 All the drugs ionize at plasma pH (i.e. Polar , Hydrophilic Drugs);
can not penetrate the Lipoidal cell membrane
1.TISSUE PERMEABILITY OF DRUGS
A. Physicochemical Properties of drugs of the drug
3) O/W permeability
 Polar and hydrophilic drugs are less likely to cross the cell
membrane
Whereas,
 Nonpolar and hydrophobic drugs are more likely to cross the
cell membrane

EFFECTIVE KO/W = Fraction unionized at pH 7.4 x KO/W of

unionized drug

 In case of polar drugs where permeability is the rate-limiting

step in the distribution , the driving force is the effective
partition coefficient of drug ► that can be calculated by above
formula.
1.TISSUE PERMEABILITY OF DRUGS
A. Physicochemical Properties of drugs of the drug
3) O/W permeability (cont’d)
 Lipoidal drug penetrate the tissue rapidly. Among
drugs with same Ko/w but different in ionization at
blood pH, one which has less ionization show better
distribution, e.g. Phenobarbital > Salicylic Acid. Both
have the same Ko/w, but Phenobarbital is more
unionized at blood pH.
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
1) The simple capillary endothelial barrier
 Capillaries supply the blood to the most
inner tissue
 All drugs ionized or unionized, molecular
size less than 600 Dalton diffuse through
the capillary endothelium to interstitial fluid
 Only drugs that are bound to blood
components cannot pass through this
barrier because of larger size of the
complex
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
2) The simple cell membrane barrier
 Once the drug diffuse through capillary to
extracellular fluid, its further entry into cells of
most tissue is limited.
 Simple cell membrane is similar to the lipoidal
barrier (absorption).
 Non polar & hydrophobic drugs will passes through
it (passively).
 Lipophilic drugs with 50-600 Dalton molecular size
& hydrophilic, polar drugs with < 50 Dalton will pass
this membrane.
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
3) The blood brain barrier
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
3) The blood brain barrier
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
3) The blood brain barrier (cont’d)
 Capillary in brain is highly specialized & much less permeable
to water soluble drugs.
 ENDOTHELIAL CELLS:- Tightly bonded with each other by
intracellular junctions.
 ASTROCYTES:- present at the base of endothelial tissue act as
supporting material & form an envelop around the capillary
thus intercellular passage gets blocked.
 BBB is lipoidal barrier, thus drugs with high o/w partition
coefficient diffuse passively while others (moderately lipid
soluble and partially ionized molecules) pass slowly.
 Polar natural substance (sugar & amino acid) are transported
to brain actively thus structurally similar drugs can’t pass the
BBB easily.
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
DIFFERENT APPROACHES TO CROSS BBB
A) Permeation Enhancers:- Dimethyl Sulfoxide
B) Pro-Drug Approach:- Dopamine ► Levodopa
(Parkinsonism) and osmatic disruption of the BBB by
infusing internal carotid artery with Mannitol
C) Carrier system:- Dihydropyridine (lipid soluble) moiety
redox system (highly lipophilic & cross the BBB)
complex formation (DRUG-DHP). After entering in
brain DHP gets metabolize by (CNS) enzyme in brain
and drug gets trapped inside the brain.
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
4) Cerebral Spinal Fluid Barrier
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
4) Cerebral Spinal Fluid Barrier (cont’d)
 Capillary endothelial cells:- have open junctions or gaps
so, drugs can flow freely b/w capillary wall & choroidal
cells.
 Choroids plexus:- major components of CSF barriers
are choroidal cells which are joined with each other by
tight junctions forming the blood-CSF barrier (similar
permeability to BBB)
 Highly lipid soluble drugs can easily cross the blood-
CSF barrier but moderately soluble & ionized drugs
permeate slowly.
 Mechanism of drug transport is similar to CNS & CSF
but the degree of uptake may vary significantly.
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
5) Placental barrier
B. Physiological Barriers
5) Placental barrier
B. Physiological Barriers
5) Placental barrier:- It’s the barrier b/w Maternal &
Fetal blood vessels.
 Both are separated by fetal trophoblast basement
membrane & endothelium.
 Thickness is 25μ at early pregnancy later reduces up
to 2μ (even its effectiveness remain unchanged)
 Molecular weight <1000 Dalton & moderate to high
lipid solubility drugs like ► (Sulfonamides,
Barbiturates, Steroids, Narcotics & some Antibiotics)
cross the barrier by Simple Diffusion rapidly
 Essential Nutrients for fetal growth are transported by
carrier-mediated processes.
 Immunoglobulins are transported by endocytosis.
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
5) Placental barrier (cont’d)
 Drugs are dangerous to the fetus at TWO stages:-
– It is advisable to avoid drugs during 1st
trimester (fetal organ development) some drugs
produce teratogenic effect e.g. Phenytoin,
methotrexate
– Later stage pregnancy affect physiological
functions like respiratory depression e.g.
morphine
– Better to restrict all drugs during pregnancy.
1. TISSUE PERMEABILITY OF DRUGS
B. Physiological Barriers
6) Blood - Testes barrier
 This barrier not located at capillary endothelium
level, but at sertoli - sertoli cell junction. It is the
tight junction / barrier b/w neighboring sertoli cells
that act as blood-testis barrier.
 This barrier restrict the passage of drugs to
spermatocytes & spermatids.
2. ORGAN TISSUE & PERFUSION RATE
 Perfusion Rate:- is defined as the volume of
blood that flows per unit time per unit volume
of the tissue (ml/min/ml).
 Perfusion rate - limited by/when:
1) Drug is highly lipophilic
2) Membrane across which the drug is
supposed to diffuse
 Above both the cases the greater the blood
flow, the faster the distribution.
Organ perfused Blood flow Organ mass Normalized blood
(mL/min) (kg) flow
(mL/min/kg)
Liver 1700 2.5 680
Kidney 1000 0.3 3333
CNS 800 1.3 615
Myocardium 250 0.3 833
Fat 250 10 25
Other (muscle) 1400 55.6 25
Total 5400 70
2. ORGAN TISSUE & PERFUSION RATE
 Distribution is permeability rate-limited in following
cases:
– When the drug is ionic/polar/water soluble
– Where the highly selective physiology barrier restrict
the diffusion of such drugs to the inside of cell.
 Distribution will be perfusion rate-limited:
– When the drug is highly lipophilic
– When the membrane is highly permeable
 It is defined as the volume of the blood that flows per
unit time per unit volume of the tissue.
Unit: ml/min/ml
(Distribution Rate Constant) Kt = perfusion rate / Kt/b
Distribution half life = 0.693/Kt =0.693Kt/b/perfusion
rate Kt/b tissue/blood partition coefficient
2. ORGAN TISSUE & PERFUSION RATE
 Highly lipophilic drugs can cross most selective barriers
like BBB, e.g. thiopental
 Highly permeable capillary wall permits passage of
almost all drugs (except those bound to plasma protein).
 Highly perfused tissues Lungs, Kidneys, Liver, Heart, Brain
are rapidly equilibrated with lipid soluble drugs.
 Drug is distributed in a particular tissue or organ depends
upon the size of tissue (Volume) & Tissue/blood partition
coefficient, e.g. Thiopental IV (lipophilic drug) & high
tissue/blood partition coefficient towards brain & adipose
tissue
 But brain is highly perfused organ so drug is distributed
fast and shows rapid onset of action than poorly perfused
adipose tissue.
3. Binding of drug to blood and other tissue
components
A. Binding of drugs to blood components o Blood
cells o Plasma proteins

B. Binding of drugs to extra vascular tissues

3. Binding of drug to blood and other tissue
components
A) Binding of drug to blood components
i) Plasma protein bindings
• Human serum albumin:- all types drug
• ά1- acid glycoprotein:- basic drugs (imipramine)
• Lipoproteins:- basic, lipophilic drugs (chlorpromazine)
• ά1-Globulin:- steroids like corticosterone , vit-B12
• ά2-Globulin:- vit-A, D, E, K, cupric ions
• Hemoglobin:- phenytoin, phenothiazines
ii) Blood cells bindings
• RBC: 40% of blood comprise of blood cells out of that
95% cells are RBC (RBC comprise of hemoglobin).
Drugs like, phenytoin, phenobarbitone binds with Hb;
imipramine, chlorpromazine binds with RBC cell wall.
3. Binding of drug to blood and other tissue
components
B) Binding of drug to blood cells
 The major component of blood is RBC
 The RBC comprises of 3 components each of which
can bind to drugs:
a) Hemoglobin
b) Carbonic Anhydrase
c) Cell Membrane
3. Binding of drug to blood and other tissue
components
C) Binding of drug to plasma proteins
 The binding of drug to plasma protein is reversible
 The extent or order of binding of drugs to various plasma
proteins is: Albumin >α1-Acid Glycoprotein> Lipoproteins >
Globulins
Human Serum Albumin
 Most abundant plasma protein with large drug binding capacity
 Both endogenous compounds and drugs bind to HSA
 Four different sites on HSA:
– Site I: warfarin and azapropazone binding site
– Site II: diazepam binding site
– Site III: digitoxin binding site
– Site IV: tamoxifen binding site
3. Binding of drug to blood and other tissue
components
D) Binding of drug to tissue components
Extra Vascular Tissue Proteins
 40% of total body weight comprise of vascular tissues
 Tissue-drug binding result in localization of drug at
specific site in body and serve as reservoir
 As binding increases it also increase biological half
life.
 Irreversible binding leads to drug toxicity.
(carbamazepin-autoinduction)
 Liver>kidney>lungs>muscle>skin>eye>bone>hair, nail
3. Miscellaneous Factors
 Age:
a) Total body water
b) Fat content
c) Skeletal muscles
d) Organ composition
e) Plasma protein content
 Pregnancy
 Obesity
 Diet
 Disease states
3. Miscellaneous Factors
a) AGE
• Difference in distribution pattern is mainly due to Total body
water - (both ICF & ECF); greater in infants
• Fat content - higher in infants & elderly
• Skeletal muscle - lesser in infants & elderly
• Organ composition – BBB is poorly developed in infants &
myelin content is low & cerebral blood flow is high, hence
greater penetration of drug in brain
• Plasma protein content - low albumin in both infants & elderly
b) PREGNANCY:- During Pregnancy, due to growth of UTERUS,
PLECENTA, FETUS ►Increases the volume available for distribution
drug. Fetus have separate compartment for drug distribution, plasma
& ECF Volume also increase but albumin content is low.
c) OBESITY :- In obese persons, high adipose (fatty acid) tissue so
high distribution of lipophilic drugs.
3. Miscellaneous Factors (cont’d)
d) DIET:- A diet high in fats will increases free fatty acid levels in
circulation thereby affecting binding of acidic drugs (NSAIDs to
albumin)
e) DISEASE STATES:- mechanisms involved in alteration of drug
distribution in disease states. i) Altered albumin & other drug-binding
protein concentration. ii) Alteration or reduced perfusion to organ or
tissue iii) Altered tissue pH. iv) Alteration of permeability of
physiological barrier (BBB) E.g. BBB (in meningitis & encephalitis)
BBB becomes more permeable to polar antibiotics like ampicillin,
penicillin G.
f) DRUG INTERACTION:- Displacement interaction occurs when two
drugs administered which having similar binding site affinity e.g. A.
Warfarin (Displaced Drug) & B. Phenylbutabutazone (Displacer)
Apparent Volume Of Distribution
 VOLUME OF DISTRIBUTION: The apparent volume of
distribution is a proportionality constant relating the plasma
concentration to the total amount of drug in the body.
X=Vd.C
Vd=X/C
 Apparent volume of distribution = amount of drug in the
body/ plasma drug concentration
 Apparent volume of distribution is dependent on
concentration of drug in plasma.
 Drugs with a large apparent volume are more concentrated
in extra vascular tissues and less concentrated
intravascular.
Apparent Volume Of Distribution
 In certain pathological cases, the Vd for the drug may be
altered if the distribution of the drug is changed.
Vd=X/C
Vd=X0 /Co
= i.v. bolus dose/concentration of drug in plasma for
drugs given as i.v. bolus:
Vd(area)=X0/KE(AUC)
 For drugs administered extravascularly: Vd(area) = FXo/
KE(AUC)
Reference:-
 Applied Biopharmaceutics and Pharmacokinetics
by Leon Shargel
 Clinical Biopharmaceutics and Pharmacokinetics
by Gibaldi
 Biopharmaceutics and Pharmacokinetics by
Brahmankar
Drug metabolism :
Biotransformation
Drug metabolism : Biotransformation
 The chemical modification of drugs with the overall
goal of getting rid of the drug
 Enzymes are typically involved in metabolism

Biotransformation is enzyme
catalyzed chemical alteration of the
drug in the body.
Drug metabolism

Metabolism
More polar
Excretion
Drug (Water soluble)
Drug
Sites of drug metabolism
 Metabolism occurs in many tissues
 E.g. brain, kidney, lung, plasma, intestine.

But mostly in the liver because…..

all of the blood in the body
passes through the liver.
Consequences of drug metabolism
 The metabolite may have…
No or reduced activity (inactivation)
 Most drugs and their active metabolite are rendered
inactive.
 Examples:- Phenobarbitone, Morphine,
Chloramphenicol, Propranolol.
Hydroxyphenobarbitone
Phenobarbitone
(inactive)
Consequences of drug metabolism
 The metabolite may have…
 Equal activity to the drug
 Many drugs have been found to be partially
converted to active metabolites.
 Examples:

Active drug Active metabolite

Diazepam Oxazepam
Codeine Morphine
Consequences of drug metabolism
The metabolite may have…
 Increased activity (Prodrug)
Prodrug
Prodrugs refer to precursor drug that in itself has little or no
biological activity and is metabolised to pharmacologically
active metabolite.

Features::
• Toxic properties not seen with the parent drug
• Stable drug
• Better PK profile and bioavailability.
First Pass Effect
 Biotransformation of drug by liver or gut enzymes
before compound reaches systemic circulation
 Results in lower systemic bioavailability of parent
compound, diminished therapeutic response.
 First pass effect may be bypassed if the drug is
administered IV or Sublingually.

 Examples: Propafenone, Isoniazid, Propranolol

Drug Metabolising Enzymes
 Microsomal
 Non-microsomal
 Non-enzymatic biotransformation
  Microsomal cytochrome P450,
Microsomal monooxygenase family of enzymes,
which oxidize drugs.
Enzymes  Location - smooth endoplasmic
reticulum in Liver, Kidney, intestinal
mucosa, and lungs.
 They catalyze:
– Oxidation, reduction, hydrolysis
(phase I reactions)
– Glucuronide conjugation (phase
II reactions)
Cytochrome P450
 Microsomal enzyme ranking first among Phase I
enzymes with respect to catalytic versatility
 Heme-containing Proteins Complex formed between
Fe2+ and CO
 Absorbs light maximally at 450 (447-452nm)
 Overall reaction proceeds by catalytic cycle:

RH + O2+ H++ NADPH ROH + H2O + NADP+

Cytochrome P450
DEFINITIONS
 Substrate: Drug is metabolised by the enzyme system

 Inducer: Drug that will increase the synthesis of CYP450

enzymes

 Inhibitor: Drug that will decrease the metabolism of a

substrate
Cytochrome P450 Expression

 Specific forms of CYP 450 are classified into

– Families designated by numbers…
– Subfamilies designated by letters… based on amino
acid sequences
– Genes by another number
 At least 15 P450 enzymes have been identified in human
liver microsomes
Cytochrome P450 Nomenclature

Famil
y

CYP2D6
Individual
Gene
Subfamily
Enzyme characteristics

 % of drugs metabolised by enzyme

– 3A4 60%
– 2D6 25%
– 1A2 15%
– 2C9 Small no. but significant interactions
– 2C19 Small no. but significant interactions
– 2E1 ???
Cytochrome P450 Expression

 Variation in levels, activity due to:

– Genetic polymorphism
– Environmental factors: Inducers, inhibitors, disease
– Multiple P450’s can catalyze same reaction
– A single P450 can catalyze multiple pathways
  Location:
• Cytoplasm, mitochondria of
Non-microsomal hepatic cells.
 Examples:
Enzymes • Monoamine oxidases (MAO),
Esterases, Amidases,
Transferases, Conjugages
 Reaction catalysed are all Phase II
reactions except_?..._____
 These are noninducible
 May show genetic variations
  Hoffman’s Elimination
 Examples:
Non-enzymatic • Some drugs like Atracurium
(skeletal muscle relaxant) are
Bio metabolized in plasma through
molecular rearrangement
transformation without involvement of enzyme
action.
BIOTRANSFORMATION REACTIONS

 Nonsynthetic / Phase I:
– Metabolite may be active or inactive
 Synthetic / Phase II:
– Metabolite is mostly inactive (conjugation)
Comparing Phase I & Phase II Reactions

Enzyme Phase I Phase II

Type of reaction Oxidation Conjugations
Reduction
Hydrolysis
Increase in Small Large
hydrophilicity
General mechanism Exposes functional Polar compound
group added to functional
group
Consequences May result in Facilitates excretion
metabolic activation
Phase I reactions: Oxidation
 Addition of oxygen (-ve charged radical) or removal of
hydrogen (+ve)

Microsomal oxidation Non-microsomal oxidation

• Hydroxylation • Mitochondrial oxidation
(phenobarbitone to (Epinephrine by MAO)
Hydroxyphenobarbitone) • Cytoplasmic oxidation
• Oxygenation (Alcohol by alcohol dehydrogenase)
• Deamination • Oxidative deamination
(Histamine)
• Dealkylation
Phase I reactions: Reductions
 Azo reduction (Microsomal)) e.g.: prontosil to sulfanilamide

 Carbonyl reduction (Non microsomal) Alcohol

dehydrogenase (ADH)
• Chloral hydrate is reduced to trichloroethanol
Phase I reactions: Hydrolysis
 Carboxyesterases (Non microsomal))
• Hydrolysis of esters : procaine to PABA by plasma
cholinesterases
Phase II reactions: Conjugations

Microsomal Non-microsomal
• Glucuronide conjugation • N acetyl conjugation
• Sulfate conjugation
• Methyl conjugation
• Glutathione conjugation
Phase II: Glucuronide Conjugations
 Parent drug or their phase I metabolite that contain
phenolic, alcoholic, carboxylic group undergoes
conjugation with uridine diphosphate glucuronic acid
(UDPGA).
 Catalytic enzyme : UDP –glucuronyl transferase
• yield drug- glucuronide conjugates that are polar.
 Examples : Diazepam, Morphine, Paracetamol,
Sulphonamides
UDPGT
Drug + UDPGA Drug glucuronide + UDP
Phase II: Non-microsomal Conjugations
Conjugation reaction Enzyme Examples
N acetyl conjugation N-acetyltransferase Dapsone
Sulphonamides
Histamine

Sulfate conjugation Sulfotransferase Paracetamol

Corticosteroids

Methyl conjugation Transmethylase Catecholamines

(minor pathway)
Enzyme Induction
Enzyme Induction
 Several drugs (inducers) induce the growth of
smooth endoplasmic reticulum leading to enhanced
microsomal enzyme activity
– Accelerates metabolism
– Decrease pharmacological response of not
only the inducer itself but also of the
coadministerd drug (substrate)
 Occurs gradually over 1-2 weeks
Enzyme Induction
Enzyme inducer Enzyme induced Substrates
Phenobarbitone CYP3A4 Midazolam
Phenytoin Macrolides
carbamazepine Calcium channel
blockers
Rifampicin CYP3A4 & Oral
Phenobarbitone CYP2C9 contraceptives
Warfarin
Clinical importance
 Increased drug metabolism:
– Decreased plasma levels and therapeutic effects of
the substrate (co-administered drug)
– Increase drug activity if the metabolite is active
– Examples : OC pills , Warfarin (therapeutic failure)
 Therapeutic use of enzyme induction

Treatment of neonatal jaundice: Phenobarbitone induces foetal

glucuronyl transferase which catalyses conjugation of bilirubin
Enzyme Inhibition
 Often rapid, reversible and relatively short acting.

 e.g. Erythromycin and Terfanadine

– Erythromycin causes a rapid increase in plasma
Terfenadine concentration if given concurrently.

 Note: Erythromycin is a substrate and an inhibitor of

CYP 3A4.
Some Enzyme Inhibitors
 Cimetidine
 Fluoxetine
 Erythromycin
 Chloramphenicol
END!!!