GENETIC POLYMORPHISM IN

DRUG TRANSPORT AND DRUG

TARGETS

Annette M.F George

Arun Kumar
INTRODUCTION

GENETIC POLYMORPHISM
Existence of inter-individual differences in the DNA
sequences coding for one specific gene, giving rise to
different functional and morphological traits.

PHENOTYPE
Observable structural and functional characteristics
of an organism determined by its genotype and
modulated by its environment.
GENOTYPE
Genetic constitution of an organism as revealed by
genetic or molecular analysis, the complete set of genes
possessed by a particular organism, cell, organs

PHARMACOGENETICS
Monogenetic variants that effect drug response

PHARMACOGENOMICS
Entire spectrum of genes that determine drug efficacy and
safety.
 POLYMORPHISMS IN DRUG TRANSPORT

• Certain membrane spanning proteins facilitate drug

transport across GIT, drug excretion into bile and urine
and the drug distribution across the blood brain barrier.

•Genetic variations for the drug transport proteins affects

the distribution of drugs and the drug concentrations at the
site of action.
• P-GP is one of the transport proteins that exhibits the

genetic polymorphism.
 P-GP is one of the product of MDR-1 gene , which is
efflux transporter in oral drug absorbtion, distribution
and urinary and biliary excretion of the drugs.

 It has the functions of –

 Exporting the anti cancer agents from cancer cells.
 Promoting multi drug resistance to chemotherapy
 Protective role by transporting toxic substrates out of

cells by its location in intestinal enterocytes,

hepatocytes etc.
EFFECT OF P-GP

It affects the distribution of drugs as

 Digoxin
 Immunosuppressants
 cyclosporine
 Tacrolimus
 antiretroviral protease Inhibitors.
 A number of polymorphisms are seen in MDR1 gene

 Common SNP’s which causes polymorphism occur

in exons 12, 21 and 26 of MDR1 gene.

 The MDR1 exon 21 and 26 polymorphs affect plasma

digoxin concentrations in patients with cardiac
arrythmias, heart failure and digoxin dosing.

 The MDR1 exon 26 polymorphism is associated with

plasma concentrations of protease Inhibitors in
patients with HIV.
 So after therapy for 6 months with Efavirenz/
Nelfinavir more CD4 cell counts observed in
individuals with exon 26 TT genotype [wild]
COMPARED WITH those without.

 Other examples of drug transporting proteins are

 Dipeptide transporters
 Org anion/ cation transporter
 L-amino acid transporter.
B] GENETIC POLYMORPHISM IN DRUG
TARGETS
 Genetic polymorphism occurs for drug target proteins
[receptors/enzymes/ion channels ] and for which
changes in drug effect occurs.

 Drug target genes may work along with genes that

affect PK properties to contribute to overall drug
response.

 Exs are that of polymorphisms in -adrenergic

receptors and their sensitivity to -agonists in
asthmatics, angiotensin converting enzyme (ACE) and
its sensitivity to ACE inhibitors, sulphonyl urea
receptor and response to OHA’s.
 DRUG EFFECT ASSOCIATED WITH
GENE [exon] DRUG/DRUG CLASS POLYMORPHISM
Blood pressure reduction and clinical
α-Adducin Hydrochlorothiazide outcomes
ACE Inh Blood pressure reduction, regression of left
ACE ventricular Hypertrophy
Angiotensinogen ACE Inh Blood pressure reduction

B1 receptor B- Blockers Blood pressure lowering

B2 receptor B- Blocker Bronchodialtion

D2 receptor Levodopa Cough

D3 receptor Levodopa dyskinesias

Estrogen receptor Estrogen Bone mineral density

 ADVANTAGES
 Sensitivity to specific medications analysed as gene
sequence varies among individuals. Eg ACE Inh

 Genetic polymorphisms that underlie disease

pathogenesis can also be major determinants of drug
efficacy

Eg- mutations in the apolipoprotein E gene and

responsiveness of patients with Alzheimer's disease to
tacrine therapy.
• Risk of adverse drug effects has been linked to
genetic polymorphisms that predispose to toxicity

Eg- dopamine D3 receptor polymorphism and the

risk of drug-induced tardive dyskinesia , potassium
channel mutations and drug-induced dysrhythmias etc
B1] RECEPTOR GENOTYPES AND DRUG RESPONSE
 The β1 and β2 receptor genes has been the focus to β

agonist and antagonists.

 B1 receptors- located on heart, kidney- lowers BP.

 There is variation in response to BP lowering agents at

alleles 49 and 389.

 The HTN patients having ‘Ser 49 and Arg 389 alleles’’

were found to have greater reduction in BP than ‘Gly 49
and Gly 389’’.

 This data suggests that B1 genotypes is important

determinant of BP lowering.
 A significant percentage fo HTN patients fail to
achieve adequate BP control with β blockers alone, so
finding genotype is important.

 β-Blockers continued in patients who respond well to

β blockers while other class of drugs used if no
response.

 β2 receptors are located on the bloodvessel, smooth

muscles- brochoconstriction and vasodilation.

 Inh β2 agonists most effective for reversal of

bronchospasm, but effects varies among people
 More than 11 SNP’s are identified in B2 receptor genes of
which 3 occur commonly.

 Two occur at alleles 16 and 27 and third occur in genes

promotor region.

 Three investigators studied influence of B2 receptor at 16 on

vasodilation ---

• 2 of 3 groups showed that Arg genotypes increase vasodilation.

• 1 showed that Gly receptors increase vasodilation.

• Another group showed that combination of SNP’s in promoter

region and former- increase vasodilation
 So it shows multiple receptor gene variations
correlates with B2 receptor receptor.

Ex 2- Clozapine is example of drug with evidence of

multiple receptor genes to show effect.

 Clozapine is for Schizophrenia in histamine and

serotonin 2A and 2C receptor genes gives 97%
response- showing that combination of polymorphs
rather than single shows response.

B2] ENZYME GENES AND DRUG RESPONSE

 The ACE is ex of enzyme with genetic contribution
to drug response.
 ACE Inh most commonly prescribed drug for HTN but
only 50% shows response to it.

 Investigators examined whether ACE [I/D]

polymorphism contributes to interpatient variability in
ACE response
Some showed greater BP reduction with I genotype
Some showed with D genotype
Others found no association

 Single polymorphism contributes little response to but

rather combination of Multiple gene polymorphism in
RAAS.
 ADR’s- the ACE I/D polymorphism was conducted
with ACE Inh induced cough in 1 study. Many
studies found no association but benefit- risk
assessment should done.
 If serious ADR’s as 1-2%, then discontinue it.

B3] GENES FOR INTRACELLULAR

SIGNALLING PROTEINS , ION
TRANSPORTERS AND RESPONSE
 Cellular response to drugs mediated by GTP binding

proteins
 B1 receptor is ex of G protein coupled receptor

where stimulatory G Protein couples with receptor-

cellular response.
 The Gs protein have alpha, beta, gamma subunits-
activation of adenylcyclase- CAMP generation-
response.

Investigation to find if alpha subunit gene interacts

with B blockers.
B4] DISEASE ASSOCIATED GENES
 Genetic variations have been associated with

predisposition to diseases and variations in drug

responses.
 Commonly gel electrophoresis based genotyping as

polymerase chain reaction coupled with restriction

fragment length polymorphism, flurescent dye etc
used.
 Numerous gene correlated with diseases with

diseases and many of these influence response to

disease managment.
 Some examples are-
 Factor V and prothrombin genes and OC’s
 Drug induced Torsades de Pointees[ Astemizole- ion

flux transport ]

 Mutation in genes for channel proteins that effect K

and Na transport across cardiac cell membrane causes
the disease.
THANKYOU