Pharmacogenetics is the study of how genetics affect individual responses to drugs. Variations in genes like CYP2D6, G6PD, and TPMT can determine drug metabolism and toxicity. Knowing a patient's genetic profile allows doctors to determine the right drug, dosage, and treatment schedule to maximize effectiveness and minimize adverse reactions. For a boy with leukemia, testing revealed a genetic variation that impacts thiopurine metabolism. His doctors were able to adjust his chemotherapy accordingly, preventing toxic side effects and allowing continued treatment. Pharmacogenetics aims to personalize drug therapy based on a patient's unique genetic makeup.

1. Pharmacogenetics
BY
QADARDANA KAKAR
BS 8TH SEMESTER
BIOTECHNOLOGY
30th OCTOBER 2016

2. Pharmacogenetics
• Pharmacogenetics has been defined as the study of variability in drug response
due to heredity.
• The history of pharmacogenetics stretches as far back as 510 B.C.
• when Pythagoras noted that ingestion of fava beans resulted in a potentially fatal
reaction in some, but not all, individuals.

3. Pharmacogenetics
Determining
The right drug
In the right dosage
At the right time
For each and ever patient.

4. Pharmacogenetics
• Variation within the human genome is seen about every 500±1000 bases.
• There are a number of different types of polymorphic markers.
• Most attention recently has focused on single nucleotide polymorphisms (SNPs,
pronounced snips).
• The potential for using these to determine the individual drug response profile is
very high.

5. Example of different response to drugs
• Primaquine-induced hemolytic anemia among African-Americans
• Later shown to be due to glucose-6-phosphate dehydrogenase [G6PD] variant
alleles.
• succinylcholine-induced prolonged apnea during anesthesia (due to autosomal
recessive butyrylcholinesterase deficiency).
• Severe adverse effects after antituberculosis treatment with isoniazid (later
shown to be due to N-acetyltransferase [NAT] variant allele).

6. Initiation of pharmacogenetics
• In 1977 the hepatic cytochrome P450 oxidase that controls debrisoquine and
sparteine metabolism were study.
• And family studies identified specific drug metabolism phenotypes
• suggested that the “poor metabolism” trait was inherited in an autosomal
recessive Mendelian fashion.

7. Continue..
• The responsible enzyme, CYP2D6, was eventually purified, cloned, and
extensively sequenced
• And is now believed to be directly involved in the metabolism of ~25% of all
commonly used drugs.
• More than 80 variant CYP2D6 alleles have since been discovered worldwide,
many of which encode deficient enzyme activity.

8. Case study
• For ten-year-old leukaemia patient Jason Saunders, the usual chemotherapy was
not going to work.
• Given the standard drug treatment, there was a strong chance that toxic
metabolites would build up in his body and make him sick.
• Requiring a break in his therapy that would allow the cancer to return.
• This is because Jason is one with a genetic variation that reduces his ability to
metabolize thiopurines,
• The drugs most commonly used to treat acute lymphoblastic leukaemia.

9. Case study
• Rather than having two high-activity copies of the TPMT gene that produces the
enzyme responsible for metabolizing these drugs, Jason has only one.
• Luckily for him, the doctors knew that.
• When he was diagnosed with cancer, one of the first things his physicians did was
take a sample of his blood to assess how he might respond to the drugs.
• As a result, Jason was given a lower dose of thiopurines than normal, and he
tolerated the therapy without needing a break. He is now in remission.

10. Conclusion
• These are important issues that will require clinical pharmacological expertise to
investigate.
• Inevitably, it is likely that many of our expectations may be unrealistic, and what
may eventually be realized is somewhere in between the viewpoints of the
optimists and pessimists.