Pharmacology - Pharmacogenomics

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Define Pharmacogenomics

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- knowledge of a pts DNA sequence could be used to optimize drug efficacy and reduce AE

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Types of Genetic Variation

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1. Pharmacokinetic: variation in proteins involved in drug metabolism or transport

2. Pharmacodynamic: variation in drug targets

3. Variation in proteins associated w/ idiosyncratic drug effects

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Pharmacokinetics

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- most common factor responsible is genetic variation in enzymes that catalyze drug metabolism

- almost all major enzymes involved in drug met. display clinically significant polymorphisms

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Genetic Polymorphisms

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- Butyrylcholinesterase (BChE)
- N-acetyltransferase 2 (NAT2)
- Cytochrome P450 2D6 (CYP2D6)
- Thiopurine S-methyltransferase (TPMT)

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BChE Polymorphism

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- BChE hydrolyses ACh
- Pts w/ variations in BChE have dec rate of metabolism of the muscle relaxant succinylcholine --> paralysis after drug exposure

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NAT2 Polymorphism

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- NAT2 catalyzes the acetylation of isoniazid and other drugs
- Pts treated w/ isoniazid can be classified as: slow acetylators (high blood drug levels b/c they met isoniazid slowly) and fast acetylators (low blood drug levels)
- Slow type = drug toxicity

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NAT2 Polymorphism Toxicity Examples

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- Hydralazine
- Procainamide-induced lupus
- Isoniazid-induced neurotoxicity

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CYP2D6 Polymorphism

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- Originally described when studying debrisoquine (anti-HTN) and sparteine (oxytotic agent)
- poor metabolizers are homozygous for recessive alleles coding for enzymes w. low activity
- Extensive metabolizers are heterozygous for "wild type"
- Some are ultrarapid metabolizers (can have multiple copies of gene)
- Caucasians worse than East Asians at metabolizing

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CYP2D6 Polymorphism - what does CYP2D6 metabolize?

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- metoprolol (B-blocker)
- haloperidol (neuroleptic)
- opioids (codeine and dextromethorphan)
- fluoxetine, imipramine, desipramine (antidepressants)

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CYP2D6 Polymorphism - Poor metabolizers

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- suffer AE when treated w/ std doses of drugs such as metoprolol
- codeine is ineffective bc it needs to be metabolized to morphine to be effective

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CYP2D6 Polymorphism - Ultrarapid metabolizers

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- require high doses of drugs
- can overdose w/ codeine, suffering resp depression or even resp arrest in response to std doses

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Thiopurine S-methyltransferase (TPMT) Polymorphism

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- TPMT catalyzes S-methylation of the anticancer thiopurines 6-mercaptopurine and azathioprine
- Thipurines have narrow TI and some pts suffer life-threatening myelosuppression
- Caucasians: most common variant for TPMT = TPMT*3A: assoc w/ low TPMT activity
- Homozygotes for TPMT*3A - inc risk for myelosuppression w/ std doses of thiopurines
- TPMT*3A rare in E. Asian (*3C)

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Variation in Drug Targets: Pharmacodynamics

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- can occur as a result of variation in germ-line DNA or, in the case of cancer, thru variation in somatic DNA

- 5-lipoxygenase polymorphism
- Epidermal Growth Factor Receptor polymorphism

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5-lipoxygenase Function

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- metabolism of arachidonate by lipoxygenases results in production of leukotrienes (implicated in asthma)
- inhibitors of the enzyme 5-lipoxygenase used to treat asthma

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5-lipoxygenase Polymorphism

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- 5-lipoxygenase encoded by gene ALOX5 which displays a variable # of tandem repeats (most common w/ 5 repeats)
- homozygous for repeat other than the 'wild type' version w/ 5 repeats express less of the enzyme
- these pts respond less well to tx w/ 5-lipoxygenase inhibitors
- polymorphism doesnt seem to affect the disease process itself

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Polymorphisms and their relationship with disease

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Polymorphism need not cause a disease to influence the treatment of that disease

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Epidermal Growth Factor Receptor Polymorphism

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- EGFR overexpressed in non small cell lung cancer (NSCLC)
- Gefitinib = inhibitor of tyrosine kinase of EGFR and is approved for tx
- E. Asians respond better than Caucasians
- Pts w/ mutation in ATP-binding site of tyrosine kinase domain of receptor respond BETTER to gefitinib

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Pharmacokinetics + Pharmacodynamics: Multiple Genes

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Warfarin
- narrow TI
- wide interindividual variability

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Warfarin

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- S-warfarin = 3-5X more potent than R-warfarin
- stereoisomers metabolized by diff enzymes

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S-Warfarin metabolism - Pharmacokinetic component

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- CYP2C9 = highly polymorphic
- CYP2C9*2 and CYP2C9*3 have much lower activity than wild type CYP2C9*1
- Pts w/ variant alleles need dec doses of warfarin (have inc risk for hemorrhage)
- 5-15% of differences in warfarin dose

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S-Warfarin metabolism - Pharmacodynamic component

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- molecular target for warfarin is vitamin K epoxide reductase
- gene encoding the enzyme is VKORC1 [shows number of polymorphisms which affect warfarin dose requirement]
- 25-30% of differences in warfarin dose

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Idiosyncratic Drug Reactions

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- not caused by differences in either drug metabolism or drug targets
- result from interactions b/w drug and a unique aspect of the physiology of the pt
- ex: G6PD def

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G6PD deficiency

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- enzyme protects RBC's from oxidative injury
- most common polymorphism = G6PD A (causes 90-95% reduction of enzyme function)
- present in 10-20% of Africans (provides protection against malaria)
- Sulfonamides, antimalarials, acetaminophen, and ibuprofen cause oxidative stress on RBC and people w/ G6PD def exposed to these drugs may develop hemolytic anemia