This document discusses pharmacogenetics, which is the study of how genes influence individual responses to drugs. It provides examples of genetic variants that can impact drug metabolism and effects. Specifically, it describes how polymorphisms in CYP2C9 and CYP2D6 genes can influence an individual's response to warfarin and tamoxifen, respectively, and how TPMT polymorphisms can increase toxicity risk from thiopurine drugs. The document also discusses the potential for pharmacogenetic testing to optimize drug therapy based on a person's genetic profile.

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.