Pertemuan X [Wahyu Hendrarti]

Aplikasi adanya polimorfi pada

gen pemetabolisme obat

• Aplikasi adanya polimorfi

pada gen pemetabolisme
obat [Ismail]
 Pertemuan XI [Wahyu Hendrarti]
• Perbedaan aktivitas dan kapasitas suatu
enzim dalam menjalankan fungsinya serta
akibat adanya variasi enzim pada metabolism
obat fase I dan II
• Perbedaan aktivitas dan kapasitas
suatu enzim dalam menjalankan
fungsinya
• Akibat adanya variasi enzim pada
metabolism obat fase I dan II [Ismail]
Pertemuan XII [Wahyu Hendrarti]

• variasi reseptor dan

transporter obat

1. variasi reseptor
2. transporter obat
 Pertemuan XIII[Wahyu Hendrarti]
Farmakogenomik dalam terapi DM
• Patofisiologi dan terapi DM
• Polimorfisme gen penyandi target
obat:
• adiponektin sebagai Target
tiazolidindion
• Target Metformin, Sulfonilurea, dll.
• Implikasi klinisnya
 Pertemuan XIV[Wahyu Hendrarti]
• Farmakogenomik dalam terapi Asma
• Patofisiologi dan terapi asma
• Polimorfisme pada gen penyandi
reseptor B2 adrenergik sebagai target
obat beta agonis
• Polimorfisme pada gen penyandi
reseptor CRF-1 sebagai target obat
kortikosteroid
• Implikasi klinisnya
 Pertemuan XV[Wahyu Hendrarti]
• Farmakogenomik dalam terapi depresi
• Patofisiologi dan terapi depresi
• Polimorfisme pada gen penyandi CYP2C19
sebagai enzim pemetabolisme utama obat
antidepresan
• Polimorfisme pada gen penyandi transporter
serotonin sebagai target obat SSRI
• Polimorfisme pada gen penyandi reseptor
serotonin sebagai target obat antidepresan
• Implikasi klinisnya
 MAO

TPH2
SERT
Drug Metabolism
Drug Transport

Distribution
Drug Transport

MAO

TPH2

Sert
 Pharmacogenetics:
From DNA to Drug Treatment
The Goal of Personalized Medicine

• The Right Dose of

• The Right Drug for
• The Right Indication for
• The Right Patient at
• The Right Time.
 Pharmacogenetics &
Pharmacogenomics
• Pharmacogenetics: The role of genetics in
drug responses. [F. Vogel. 1959]

• Pharmacogenomics: The science that

allows us to predict a response to drugs
based on an individuals genetic makeup.
[Felix Frueh, Associate Director of
Genomics, FDA]
Courtesy Felix W. Frueh
 Pharmacogenetics &
Pharmacogenomics
http://www.pharmgkb.org/

• Pharmacogenetics: study of individual gene-drug

interactions, usually one or two genes that have
dominant effect on a drug response (SIMPLE
relationship)
• Pharmacogenomics: study of genomic influence on
drug response, often using high-throughput data
(sequencing, SNP chip, expression,
proteomics - COMPLEX interactions)

– PharmGKB Website: http://www.pharmgkb.org/

Courtesy of Michelle Whirl-Carillo

 Pharmacogenomics Strategy Applied to the
Practice of Medicine

GCCCGCCTC

GCCCACCTC

From McLeod and Evans, Ann Rev of Pharmacol and Toxicol, 2001: 41,101-
 Pharmacogenomics Strategy Applied to
Drug Development
Pharmacogenomics: systemic genomic
analysis in populations of treated subjects to
identify variants that predict drug response
including the occurrence of adverse reactions

Cause of DiseaseDifferential Diagnosis

Drug Discovery Drug Therapy Drug Selection

By 2010 By 2005 By 2008
Targets Dosing Class
A brief aside into modern genetics

Receptor
Transporter
Enzim
Pharmacogenetics: A Case Study

Courtesy of Michelle Whirl-Carillo

Pharmacogenetics: A Case Study

Courtesy of Michelle Whirl-Carillo

Pharmacogenetics: A Case Study

Courtesy of Michelle Whirl-Carillo

 Back to the drugs…
• The utility of pharmacogenetics:
– Determining appropriate dosing
– Avoiding unnecessary toxic treatments
– Ensuring maximal efficacy
– Reducing adverse side effects
– Developing or choosing novel treatments
– Can also explain variable response to illicit drugs
 PK Basis for Differences in Drug Response

• Extrinsic factors
– environment (smoking, diet, alcohol)
– drug interactions (Rx, OTC and herbal)
• Intrinsic factors
– demographic (gender, age, race)
– disease (renal, hepatic)
– pharmacogenetics (PGt)
• polymorphisms in genes encoding metabolic enzymes
 VeraCode ADME Core Panel
ADME Core (34 genes, 185 markers)
• Absorption
ABCB1 CYP2C9 NAT1 SULT1A1

ABCC2 CYP2D6 NAT2 TPMT

• Distribution ABCG2 CYP2E1 SLC15A2 UGT1A1

CYP1A1 CYP3A4 SLC22A1 UGT2B15

• Metabolism CYP1A2 CYP3A5 SLC22A2 UGT2B17

CYP2A6 DPYD SLC22A6 UGT2B7

CYP2B6 GSTM1 SLCO1B1 VKORC1

• Excretion CYP2C19 GSTP1 SLCO1B3

CYP2C8 GSTT1 SLCO2B1

Illumina
 Drug Metabolizing Enzymes

Phase II
Phase I Conjugation
Modification of with
functional groups: endogenous
Evans and Relling, Science 1999 substituents
Hydrolysis to form:
Oxidation
Dealkylation Glucuronide
Dehydrogenation Acetate
Reduction Glutathione
Deamination Sulfate
Desulfuration Methionine
Many CYP450 Enzymes Are Polymorphic:
Example CYP 2D6

• Responsible for
metabolism of 40%
of all Rx drugs
• Over 300 million
Rx’s for drugs with
polymorphism per
year

Family: CYP 2
Subfamily: CYP 2D6
Gene: CYP 2D6*3
 PGt and Drug Metabolism

Same dose but different plasma

concentrations
Patient A Wild type
CYP450

Concentration
GCCCGCCTC

Wild type

Time

Patient B Mutation

Concentration
CYP450
GCCCACCTC

Mutation

Time
PGt: Possible Impact on PK and Dose-Response

Efficacy: reduction in anxiety

and symptoms of depression

Example:
Nortriptyline
Safety: tachycardia,
arrhythmias and drowsiness
 Personalized Drugs
• Herceptin (breast cancer, target: Her2/neu)
• Erbitux (colorectal cancer, target: EGFR)
• Tarceva (lung cancer, target: EGFR)
• Strattera (attention-deficit/hyperactivity
disorder, Metabolism: P4502D6)
• 6-MP (leukemia, Metabolism: TPMT)
• Antivirals (i.e. resistance based on form of HIV)
• etc. and the list is growing rapidly ...