Far Eastern University – Nicanor Reyes Medical Foundation
Pharmacology A – Pharmacogenomics - Summary
Abraham Daniel Cruz M.D.
PHASE I ENZYMES
- Modify functional groups, drug biotransformation
CYP2D6
 Metabolism of ¼ of all clinically used drugs
 Accounted with 9 alleles:
 *3, *4, *5, *6 – non-functional
 *10, *17, *41 – reduced function
 *1, *2 - functional
 CYP2D6*4
 MOST COMMON NON FUNCTIONAL
 20% in Europeans
 4% Homozygous
 32% Heterozygous
 Example: Codeine
 MOA: CYP2D6 converts codeine to morphine via O-
demethylation.
 Morphine is the active metabolite of codeine, binding
to µ-opioid receptors to induce analgesia.
 EM – Normal CYP2D6, sufficient conversion
 PM, IM – Insufficient Pain Relief
 UM – Increased side effects (drowsiness,
respiratory depression)
 Adverse effects:
 GIT – constipation (PM)
 CNS – Sedation and Dizziness (PM, EM)
 Antitussive property is not affected by CYP2D6.
 Recommendations:
 EM, IM – Standard dosing w/ close monitoring
 PM, UM – Alternative agent
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CYP2C19 DIHYDROPYRIMIDINE DEHYDROGENASE (DPD)
 Metabolizes acidic drugs (proton pump inhibitors,  Encoded by DPYD Gene.
antidepressants, antiepileptic, antiplatelet).  First and rate-limiting step in Pyrimidine Catabolism
 Major elimination route for fluoropyrimidine chemotherapy
 Highly Polymorphic:
 Variations:
 *2, *3 – non functional
 *2A, *13, rs67376798 – non-functional, rare
 *1 – functional
 *2A – MOST COMMON
 *17 – increased function
 Phenotypes:
 Example: 5-Fluorouracil (5-FU)
 PM – 2 non-functional alleles
 Most active among with Capecitabine and Tegafur.
 UM – any combination of functional alleles
 Given for solid tumors especially colorectal & breast
 IM - *17 + non-functional allele (It is intermediate
 5-FU –intravenous
because *17 cannot fully compensate for the non-
functional allele).  Capecitabine, Tegafur – Oral prodrugs converted to 5-FU
 CYP2C19*2 – MOST COMMON NON FUNCTIONAL  1-3% converted to active cytotoxic (5-FUMP,
 CYP2C19*17 – Gain-of-function allele FdUMP)
 80% undergoes catabolism by DPD and excreted
 Example: Clopidogrel  Effects of complete or partial DPD Deficiency:
 It is an anti-platelet pro-drug. 1. Reduced clearance of 5-FU
 MOA: Clopidogrel irreversibly inhibits ADP-induced 2. Increased half-life of toxic metabolites
platelet aggregation 3. Increased risk for severe dose-dependent
fluoropyrimidine toxicity (myelosuppresion, H&F
 Metabolism:
 85% - active hydrolysis by hepatic esterase to its
Syndrome, Neurotoxicity, Mucositis, Diarrhea).
inactive carboxylic acid derivative.
 15% - converted by CYP-mediated reaction to
the active thiol metabolite.
 Carriers of the non-functional/reduced function:
1. Decreased active metabolite formation
2. Reduced anti-platelet activity
3. Results to CVS events (e.g. Acute Coronary
Syndrome)
EM – Extensive Metabolizers
 Recommendations:
IM – Intermediate Metabolizers
 EM, UM – standard dosing PM – Poor Metabolizers
 PM, IM – Alternative antiplatelet (prasugrel, UM – Ultra Metabolizers
tricarelor)

PHASE II ENZYMES
- Conjugate endogenous materials to enhance elimination
- Polymorphic enzymes may cause decreased excretion
and drug retention or toxicity.
UGT1A1 (Uridine 5’-diphosphoglucuronosyl transferase 1)
 Encoded by UGT1A1 gene
 Conjugates glucoronic acid into small lipophilic
molecules to enhance biliary excretion.
 UGT1A1*28 allele – MOST COMMON
 Extra TA repeats in the proximal promoter region
 Homozygous
 30% reduced activity
 60-70% increased levels of circulating
unconjugated bilirubin, reduced biliary
elimination
 Example: Irinotecan
 MOA: Topoisomerase 1 inhibitor with 5-FU and
Leucovorin for metastatic colorectal cancer.
 Hydrolyzed by hepatic enzyme to SN-28 which is the
active, cytotoxic form to terminate DNA replication
and induce cell death.
 UGT1A1*28 carriers:
 Risk factor for severe life threatening toxicity
 Due to decreased clearance of S28 metabolites
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G6PD Deficiency
 X-linked:
TPMT (Thiopurine S-Methyltransferase)
 Normal
 Covalently attaches methyl group onto aromatic and
- Male (1 normal X)
heterocyclic sulfhydryl compounds to deactivate
- Female (2 normal X)
thiopurine drugs.
 Variations:  Reduced
- Male (1 abnormal X - Hemizygous)
 *2, *3A, *3B, *3C – non-functional
- Female (2 abnormal)
 Major determinants of thiopurine metabolism,
 Heterozygous Females
efficacy, and toxicity
- One X is randomly silenced; enzyme activity can
 High activity – 2 functional TPMT
be either fully functional or severely impaired.
 Intermediate activity – 1 functional TPMT
 Class II – severe deficiency (10%)
 Low activity – 2 non-functional TPMT
 Class III- moderate deficiency (10-60%)
 Beneficial against malaria, 8% frequency in malaria
 Example:
endemic countries:
 Azathioprine (Prodrug of 6-MP)
 African allele – mild
 6-Mercaptopurine
 Mediterranean – more severe allele
 6-Thioguanine
 East Asia & Pacific – heterogenous, COMMON
 Metabolism:
 Activation: Hypoxanthine Guanine Phosphoribosyl
 Example: Rabuscirase
Transferase (HGPRTase enzyme), cytotoxic and
 MOA: Urate oxidase enzyme, initial management of
therapeutic effects.
uric acid levels in cancer patients undergoing
 Inactivation: TMPT and Xanthine Oxidase
chemotherapy.
 Converts uric acid to allantoin, releases H2O2 and can
cause oxidative stress.
Other Enzymes  G6PD Deficiency:
 Increases risk of severe hemolytic anemia and
G6PD (Glucose 6-Phosphate Dehydrogenase) methemoglobinemia due to lack of NADPH as an
antioxidant for H2O2.
 Rate-limiting step in Pentose Phosphate Pathway.
 Supplies reduced NADPH.
 In RBC, exclusive source of antioxidant.
 G6PD increases activity to meet NADPH demands to
prevent hemolysis.
Genetic Variations in Transporters Genetic Variations in Immune System IFNL3 (IL-28B)
 Membrane transporters mediate uptake and efflux of  Involve pharmacodynamics genes (receptors)  Encoded by IFNL3, or IL28B gene
endogenous substances and xenobiotics.  HLA-loci polymorphism – associated with drug  Belongs to the Type II IFN-γ cytokine.
 Influence the drug concentration and their toxicity predisposition.  Induced by viruses
metabolites  Genetic variants were associated with PEG-IGN-α in
combination with ribavirin.
OATP1B1 (Organic Anion Transporter 1B1) HLA System Polymorphisms  There is 2 fold greater cure rates in patients with
rs12979860 variant.
 Encoded by the SLCO1B1 gene.  HLA-B, -DQ, -DR is associated with:
 Located in the hepatic sinusoids and responsible for  Allopurinol
the hepatic uptake of mainly weakly acidic drugs:  Carbamazepine Polygenic Effects
 Statins  Abacavir
 Methotrexate  Flucloxacillin
CYP2C9
 rs4149056  HLA-B Polymorphism
 Phase 1 drug metabolizing enzyme
 Reduced function polymorphism  Altered antigen-binding site.
 Acts primarily on acidic drugs:
 Amino acid change, Val174Ala – reduced  May recognize different peptides
 S-warfarin
membrane expression
 Phenytoin
 *5 allele – rare  Example: Abacavir
 NSAIDs
 *15, *16, *17  Involved with drug-bound peptide appears to
 Variants:
 Halotypes with rs4149056, common in European interact with product of HLA-B*57:01.
 CYP2C9*5
and Asian.  Metabolism:
 AA change Arg144Cys
 Abacavir is transformed to carbovir
 On enzyme’s outer surface.
 Example: Statins triphosphate (Active form).
 Impairs interaction with microsomal P450
 MOA: HMG-CoA reductase inhibitor  Reactive Molecule that activates Cytotoxic CD8
oxireductase.
 Generally safe and well-tolerated but can induce Cells.
 Results to 30-40% reduced metabolism of
skeletal muscle toxicity.  Gene product bound to peptide is presented on
CYP2C9 substrates.
 Impaired OATP (rs4149056) leads to systemic cell surface with different configuration
 CYP2C9*3
exposure to simvastatin and result to muscle pain. recognized by CD8+ cells resulting to
 AA Change Ile359Leu
 Recommendation: Hypersensitivity.
 On enzyme’s interior
 Give lower dose of simvastatin
 Lowered affinity for many substrates.
 Switch to an alternative statin drug  Example: Flucloxacillin
 Results to 80-90% reduced metabolism.
 Causes hypersensitivity reactions that can lead to
 CYP2C9*2, *3
drug-induced liver toxicity.
 More common in European
 Also associated with HLA-B*57:01:
 CYP2C9*5,*6,*8,*11
 Ximegaltran (HLA-B*07:01)
 More commin in African
 Isoniazid, Rifampin, Ethambutol

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VKORC1 (Vitamin K Epoxide Reductase Complex Subunit 1)
 Responsible for recycling Vitamin K.
 Activates Vitamin K-dependent clotting factors
(9,10,7,2), Protein C, and Protein S.
 Rare variant may lead to multiple coagulation factor
deficiency Type 2A or Warfarin Resistance.
 VKORC1-1693G>A – MOST COMMON
 Reduced expression of VKORC1 in the liver
 Increased Warfarin Sensitivity
 Most important consequence of VKORC1
polymorphism

 Example: Warfarin
 MOA: Oral anticoagulant, inhibits VKORC1, prevents
activation of Vitamin K dependent factors resulting to
anticoagulative effects.
 VKORC1 Polymorphism
 -1639G>A leads to decreased VKORC1
expression, and increased risk for excessive
anticoagulation.
 CYP2C9 Polymorphism
 Warfarin is administered in R- and S-
enantiomers or racemic mixtures.
 Reduced CYP2C9 – increased risk of bleeding
due to decreased metabolic clearance of S-
warfarin.

Note: This is just a summarized version of the manual, it’s

still best to use the available transes and Doc Cruz’ PPT. 

Yeri adothraki ayyeyaan. Me nem nesa.

"You shall ride forever. It is known."

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