The document outlines pharmacogenetics and pharmacogenomics, highlighting the impact of genetic variability on drug response and personalized medicine. It discusses key aspects such as genetic polymorphisms, the role of cytochrome P450 enzymes in drug metabolism, and the relevance of drug transporters. The content emphasizes the importance of understanding individual genetic makeup to optimize drug therapy and minimize adverse drug reactions.

1. Dr. S P Srinivas Nayak,
PharmD., MSc., PGDND., (PhD)
Assistant Professor, PIPR, PU
PHARMACOGENETICS

2. Lecture Objectives
After completion of this lecture, student will be able to:
• Define pharmacogenetics and pharmacogenomics.
• Define genetic polymorphism and explain the difference between genotype and phenotype.
• Explain with relevant examples how genetic variability influences drug response, pharmacokinetics,
and dosing regimen design.
• Describe the relevance of CYP enzymes and their genetic variability to pharmacokinetics and dosing.
• List the major drug transporters and describe how their genetic variability can impact
pharmacokinetics.
• Discuss the main issues in applying genomic data to patient care, for example, clinical interpretation
of data from various laboratories and accuracy of record keeping of large amounts of genomic data.

3. INTRODUCTION
• Pharmacogenetics is the study of how genes affect the way people
respond to drug therapy
• The goal of pharmacogenetics is to individualize drug therapy to a
person's unique genetic makeup
• An understanding of an individual's genetic makeup is thought to be the
key to creating personalized drugs with greater efficacy and safety

4. Introduction
• Therefore, Pharmacogenetics is an established discipline that studies the
genetic basis of interindividual variability in the response to drug therapy, and
allows for individualization of drug therapy
• A closely related, and considered by some to be an equivalent or overlapping
field, is pharmacogenomics

5. Introduction
• Pharmacogenomics involves study of the role of genes and their genetic
variations (DNA, RNA level) in the molecular basis of disease, and therefore,
the resulting pharmacologic impact of drugs on that disease
• In general pharmacogenetics usually refers to how variation in one single
gene influences the response to a single drug
• Pharmacogenomics is a broader term, which studies how all of the genes
(the genome) can influence responses to drugs

6. Introduction
• Genes are made of DNA, and so is the genome itself. A gene consists of
enough DNA to code for one protein, and a genome is simply the sum total
of an organism's DNA

7. Introduction

8. Introduction

9. Introduction
• Application of pharmacogenetics to pharmacokinetics and
pharmacodynamics helps the development of models that predict an
individual's risk to an adverse drug event and therapeutic response
• For example, the monoclonal antibody Herceptin was designed to treat a
subset of breast cancer patients who overexpress the HER-2 (human
epidermal growth factor receptor-2) gene. Patients who lack HER-2
overexpression are considered to be nonresponders to Herceptin therapy

10. Introduction
• The outcome of disease, resistance to treatment, and adverse reactions are
increasingly recognized as an interaction of the individual's genes and the
environment
• Dominic Kwiatkowski, recently reviewed the role of genes in human
susceptibility to infection

11. Introduction
• He predicted that recent advances in genetics and genotyping technology will
make it feasible within the next decade to screen the whole genome for
genetic factors that determine susceptibility to HIV and AIDS, malaria, and
tuberculosis
• Kwiatkowski listed many genes and their encoded proteins that play roles in
immunity and disease fighting

12. Introduction

13. GENETIC POLYMORPHISMS
• Genetic polymorphisms are variations in gene sequences
that occur in at least 1% of the general population,
resulting in multiple alleles or variants of a gene
sequence.
• The most commonly occurring form of genetic variability is
the single nucleotide polymorphism (SNP, often called
“snip”)
• An example of such an effect occurs if nucleotide position 2935 of
the CYP2D6 gene has a C instead of an A (c.2935A>C). During
translation this results in the insertion of a proline instead of
histidine at amino acid position 324 generating the CYP2D6*7
allele, with no drug metabolizing activity

14. GENETIC POLYMORPHISM IN DRUG METABOLISM
• Drug metabolism is responsible for the chemical modification of
drugs or other xenobiotics that usually results in increased
polarity to enhance elimination from the body.
• The enzymes that perform drug metabolism are classified as
either phase I or phase II enzymes.
• Phase I enzymes perform oxidation, reduction, and
hydrolysis reactions while phase II enzymes perform
conjugation reactions.
• Polymorphisms have been reported in both phases of drug-
metabolizing enzymes and can affect the pharmacokinetic
profile of a drug

15. CYTOCHROME P-450 ISOZYMES
• The CYP450s are divided into families identified with
numbers (CYP1, CYP2, CYP3, etc) and subfamilies
identified with letters (CYP2A, CYP2B, etc)
• The major drug metabolizing CYP450 families are CYP1,
CYP2, and CYP3

16. CYP2D6
• CYP2D6 is the most highly polymorphic CYP with more
than 70 allelic variants reported.
• It is responsible for the metabolism of antidepressants,
antiarrhythmics, beta-adrenergic antagonists, and
opioids, which frequently have narrow therapeutic
indices.
• It is estimated that approximately 10% of the Caucasian
population, 1% of the Asian population, and between 0%
and 19% of the African population have a PM phenotype
of CYP2D6, resulting in increased plasma concentration
of the parent drug due to decreased metabolic clearance

17. DRUG EFFECT FDA INFORMATION

18. • This has been reported with the breast cancer agent
tamoxifen. Tamoxifen has an active metabolite
(endoxifen) produced by CYP2D6 that is thought to be
responsible for much of its antiestrogenic activities. The
patient with the PM phenotype would not metabolize
tamoxifen to the active metabolite and, therefore, does
not benefit from clinically relevant endoxifen
concentrations

19. CYP1A2
• CYP1A2 is responsible for the metabolism of about 5% of
marketed drugs including fluvoxamine, clozapine, olanzapine, and
theophylline. Approximately 15% of the Japanese, 5% of the
Chinese, and 5% of the Australian populations are classified as
CYP1A2 poor metabolizers.
• The most frequent allelic variant is CYP1A2*1F, which results in
an increased expression caused by an SNP in the upstream
promoter region. Enhanced enzyme levels are thought to cause
faster substrate clearance, which has been associated with
treatment failures for clozapine in smokers with the *1F allele.
CYP1A2*1C is also an SNP in the upstream promoter region that
results in decreased enzyme expression and has a prevalence up
to 25% in Asian populations

20. CYP2C9
• CYP2C9 has at least 30 different allelic variants with the two most
common being CYP2C9*2 and *3. Both of these variants result in
reduced CYP2C9 activity and are carried by about 35% of the
Caucasian population.
• CYP2C9 helps in metabolism of warfarin, if is not appropriately
lowered, then there is an increased risk of bleeding.
• It also metabolises nonsteroidal anti-inflammatory drugs,
sulfonylureas, angiotensin II receptor antagonists, and
phenytoin(because of their high therapeutic indices (except
phenytoin), do not usually result in adverse effects)

21. CYP2C19
• The CYP2C19 PM phenotype results in a lack of efficacy for
the antiplatelet prodrug clopidogrel.
• For activation, clopidogrel requires a two-step metabolism by
several different CYP450 with CYP2C19 being a significant
contributor.

22. CYP3A4
• CYP3A4 is the most abundant CYP450 in the liver and
metabolizes over 50% of the clinically used drugs.
• SNP that is found in about 2.7% of the Caucasian
population and has some decreased clearance for the
calcium channel blocker nifedipine but not for
testosterone 6β-hydroxylation.

23. Plasma pseudocholinesterase or serum
butyrylcholinesterase
• Patients with slowed metabolism of succinylcholine have
elevated blood levels, prolonged duration of action, and
prolonged apnea compared to patients with fully
functional pseudocholinesterase.
• Dihydropyrimidine dehydrogenase (DPD)
• Polymorphisms in DPD result in a loss of enzymatic activity
leading to the accumulation of the chemotherapeutic agent 5-
flourouracil (5-FU), which leads to significant toxicity including
leukopenia, thrombocytopenia, and stomatitis.

24. Thiopurine S-methyltransferase(TPMT)
• Thiopurine drugs including 6-mercaptopurine (MP) and
azathioprine are used for their anticancer and
immunosuppressive properties but can have significant
adverse effects including myelosuppression.
• The loss of TPMT function is present in about 5% of the
Caucasian population and results in accumulation of MP
leading to an increased risk for adverse effects like
leukopenia.

25. Uridine Diphosphate (UDP)-
glucuronosyltransferase
• Irinotecan is a prodrug topisomerase-1 inhibitor that is
approved to treat metastatic colon or rectal cancer. The
active metabolite of irinotecan, SN-38, is produced by
ester hydrolysis and is primarily cleared through biliary
excretion after inactivation by UGT (Rothenberg, 1998).
The accumulation of SN-38 is associated with dose- and
treatment-limiting adverse effects including bone marrow
toxicity and diarrhea

26. N-Acetyltransferase
• N-acetyltransferase (NAT) was identified as a polymorphic
enzyme through phenotypic observations of fast or slow
acetylators of the anti-tuberculosis drug, isoniazid

27. GENETIC POLYMORPHISM IN DRUG
METABOLISM : CYP P-450 ISOENZYMES

28. Genetic Polymorphism in Drug Transport
and Drug Targets
• Several membrane transporter proteins are involved in
drug absorption from the intestinal tract and distribution
through the body.
• An increased appreciation of the influence of these
transporters on the uptake and efflux of drugs into or out
of tissues has enhanced interest in the pharmacogenetics
of these transporters

29. MDR1 (P-Glycoprotein)
• The MDR1 or ABCB1 gene codes for the efflux protein P-
glycoprotein (P-gp) that is frequently associated with drug
resistance to antineoplastic agents including vincristine
and doxorubicin.

30. ABC Transporters
• The multidrug resistance-associated proteins (MRPs) are
members of the ATP-binding cassette (ABC) superfamily
with six members currently, of which MRP1 (ABCC1),
MRP2 (ABCC2), and MRP3 (ABCC3) are commonly
known to effect drug disposition.
• Like MDR, these transporters can also be expressed in
cancer cells, which confer resistance to the
chemotherapeutic agent tamoxifen

31. Solute Carrier Transporters
• Another important class of drug transporters is the solute
carriers (SLCs) such as the organic anion transporter
protein (OATP) and organic cation transporter (OCT).
• These transporters are located throughout the body and
have various roles in the transport of many different
drugs. OATP1B1 (coded by the SLCO1B1 gene) is a
hepatic influx transporter with at least 40 non-
synonymous SNPs identified that result in either an
altered expression or activity of OATP1B1

32. Summary
• Pharmacogenetics is the study of how genes affect the way people respond
to drug therapy
• Pharmacogenetics usually refers to how variation in one single gene
influences the response to a single drug
• Pharmacogenomics is a broader term, which studies how all of the genes
(the genome) can influence responses to drugs