1.  + Rx = 
 + Rx = 
 + Rx = 
People react differently to drugs!
PHARMACOGEN
ETICS

3.  Pharmacogenetics is the study of influences of a gene on therapeutic and adverse effects of
drugs.
 Primaquine induced hemolysis in patients with G6PD (Glucose-6-Phosphate Dehydrogenase
) deficiency, was the first pharmacogenetic discovery.
 The term Pharmacogenetics was coined by Vogel in 1959.
 Currently, there are over 120 drugs including warfarin, carbamazepine, azathioprine etc. whose
labeling includes pharmacogenetic discoveries.

4.  The pharmacokinetics of a drug can be changed by sequence variations in drug-disposition genes.
 The pharmacodynamics of a drug can be changed by sequence variations in drug-target genes.
i. single nucleotide polymorphisms (SNPs)
ii. insertions/deletions (indels).
TYPES OF GENETIC VARIANTS

5.  A drug’s disposition includes its absorption, metabolism, distribution, and excretion (ADME).
 The plasma concentrations of the parent drug or its active metabolites may be affected by a genetic
polymorphism changing the function of a protein that is involved in the disposition of a drug.
 Genetic polymorphism  lower activity of a metabolizing enzyme  plasma concentrations of the
parent drug may increase and plasma concentrations of metabolites may decrease.
 Parent drug exhibits pharmacologic activity, the genetic polymorphism will potentiate the drug
response, including adverse drug reactions.
 Examples:
 Warfarin and CYP2C9 polymorphisms
 Tamoxifen and CYP2D6 polymorphisms
 Thiopurine drugs and Thiopurine S-methyltransferase (TPMT) polymorphisms

6.  Large variability in the dose required to achieve
therapeutic anticoagulation
 CYP2C9 is the enzyme responsible for the
metabolism of warfarin
 SNPs exist in CYP2C9 gene that decrease the
activity of the CYP2C9 metabolizing enzyme

7.  Tamoxifen is commonly used for breast cancer
treatment.
 Endoxifen, a metabolite of tamoxifen, is 100 times
more potent than the parent drug.
 CYP2D6 is involved in generating endoxifen from
tamoxifen
 NPs exist in CYP2D6 gene that decrease the activity of
the CYP2D6 metabolizing enzyme
 CYP2D6 is responsible for the metabolism of a number
of different drugs
 Antidepressants, antipsychotics, analgesics, cardiovascular
drugs
 Over 100 polymorphisms in CYP2D6 have been
identified

8.  Thiopurine drugs are used to treat Acute
lymphoblastic leukemia
 TPMT metabolizes thiopurine drugs such as
mercaptopurine and azathioprine.
 Polymorphisms in the TPMT gene result in decreased
TPMT enzyme activity
 Decreased TPMT activity predisposes individuals to
severe, life-threatening toxicities from these drugs

9.  Genetic polymorphisms of drug-target enzyme or receptor may alter the drug
response.
 Fewer genetic polymorphisms in pharmacodynamic genes have been
recognized by FDA, including…
 ß1-adrenergic receptor gene polymorphisms (ADRB1) and ß-blocker response

10.  Ser49Gly and Arg389Gly are two common SNPs in ADRB1.
 It is hypothesized that hypertensive patients carrying Ser49 or Arg389 would have greater
reduction in blood pressure with ß-blocker therapy.
 Several studies have found that hypertensive patients with Ser49Arg389/Ser49Arg389
haplotype had the greatest reduction in blood pressure with oral metoprolol.
 Since the frequency of the Arg389 allele in ADRB1 is higher in Caucasians (73%) than in
African Americans (58%), Caucasians are more likely to have a better blood pressure response
to a ß-blocker than do African Americans.

11.  HLA gene tests
 Drug metabolism related gene test
 Drug target related gene test
 Combined (metabolism & target) gene test
Amplichip
Determine the genotype of the patient in terms of two
CYP450 enzymes: 2D6 and 2C19.
FDA approved the test on Dec 24, 2004. The Amplichip CYP450
test is the first FDA approved pharmacogenetic test.

12.  Maximize drug efficacy
 Minimize drug toxicity
 Studying drug metabolism and
pharmacological effects
 Aid in new drug development
“One-size-fits-all drugs”
only work for about 60 %
of the population at best
40 % of the population have
increased risks of ADR
because their genes do not do
what is intended of them
Right Medicine
For
Right Patient

14.  The drug response is probably affected by multiple genes.
 Drug response might be predicted from a certain pattern of polymorphisms rather than only a
single polymorphism.
 Holding sensitive information on someone’s genetic make up raises questions of privacy and
security and ethical dilemmas in disease prognosis and treatment choices.