Pharmacogenomics Flashcards
Define pharmacogenomics
Study of genetics in drug response
Pharmacodynamics
- Is the therapeutic drug target present or not, or is it in some way changed?
- Do variants in non-target gene products, those that contribute to adverse effects?
Pharmacokinetics
- For which CYPs do variants exist?
- For which phase II enzymes do variants exist?
- For which transporters do variants exist?
Define genome
The whole of the genetic information of an organism found in the nucleus of eukaryotes
Define gene
A heritable factor that can control a specific characteristic
Define alleles
Specific forms of a gene differing by one or a few bases and occupying the dame gene locus
Most of action in pharmacogenomics is at the level of alleles
Define SNP
Single-nucleotide polymorphisms: An exchange of one nucleotide pair for another
- Coding regions can be synonymous (no change in amino acid production) or nonsynonymous (change in amino acid - may not have affect on protein function, but can)
- Noncoding regions
- Exchange is stable within a population (present in >1% of population)
Name some structural polymorphisms
- Gene deletion (ABCD => ACD)
- Inverted gene sequence (ABCD => ACBD)
- Copy number variant/amplification (ABCD => AAAAABCD)
- Insertion (ABCD => ABACD)
Describe how SNPs can affect clinical outcome
- About 1 million SNPs, most won’t change pharmacokinetics/drug response
How is pharmacogenomics incorporated into drug labeling?
Appears on ~150 FDA-approved drug labels
- Genetic testing required
- Genetic testing recommended
- Actionable PGx: should consider genetic testing, significant evidence for it
- Informative: conjecture, not enough evidence
Which CYPs have meaningful polymorphisms?
CYP2C9, CYP2C19, ***CYP2D6
What is the difference between genotype and phenotype?
Genotype: how genes are written
Phenotype: how genes are expressed
Describe how genotype affects phenotypes of CYP2D6
- Ultra metabolism (UM): >2 functional alleles (see more of metabolite)
- Extensive metabolism (EM): 1-2 normal alleles
- Intermediate metabolism (IM): 2 reduced-function or 1 null allele & a reduced-function allele
- Poor metabolism (PM): 2 null alleles (no functional CYP2D6)
Discuss the most important CYP2D6 alleles
- Null alleles: cause most of PM phenotypes - *3 frameshift, *4 splice variant, *5 gene deletion, *6 frameshift
- Alleles responsible for reduced function, hence IM phenotypes: *10, *17, *41
- Alleles responsible for amplified activity, hence UM phenotypes: *1xN, *2xN
How does a UM of CYP2D6 affect metabolism of codeine?
- Codeine is a weak analgesic
- Normally, mostly metabolized by CYP3A4, small amount by CYP2D6 into morphine
- If a drug that irreversibly inhibits CYP3A4 is present, more will be directed toward CYP2D6 for metabolism more metabolized bc UM, more morphine made, phase II reactions cannot handle amount of morphine, CNS/respiratory depression
What is the bottom line for metabolism of a drug be different CYP2D6 phenotypes?
UM: small amount of inactive prodrug => large amount of active metabolite
- Increased in Cmax &/ AUC of active entity relative to other patients
PM: lots of inactive prodrug needed => small amount of active metabolism
- Decrease in Cmax &/ AUC of active entity relative to other patients
What medications have required or recommended genetic testing for CYP variations prior to initiation of drug therapy?
Required: - Pimozide = Cyp2D6 - Tetrabenzine = CYP2D6 Recommended: - Clopidogrel = CYP2C19 - Dextromethorphan + quinidine = CYP2D6 Actionable: Usually cytochromes, occasionally phase II enzymes
