L18: Pharmacogenetics and personalised medicine

What is the superfamily of monooxygenases that catalyze the oxidation of organic substances?

Cytochrome P-450 enzymes (CYP)

How many CYP enzymes are known to be involved in drug metabolism?

15

What percentage of drug metabolism is carried out by CYP2C9, CYP2C19, and CYP2D6 enzymes?

40%

What are the four possible phenotypes resulting from CYP polymorphism?

Ultrarapid or rapid metabolizer, extensive or normal metabolizer, intermediate metabolizer, poor metabolizer

What is the purpose of the AmpliChip CYP450 clinical test?

To genotype known polymorphisms in CYP2D6 and identify major variants in CYP2C19

Which CYP enzyme mediates the most drug metabolism?

CYP2D6 (20-30%)

Give an example of a drug that is metabolized by CYP2D6.

Codeine

What are the consequences of CYP2D6 polymorphism for codeine metabolism?

Poor metabolizers cannot convert codeine to morphine, while ultra-rapid metabolizers have high exposure to morphine

What is the major role of CYP2C9?

Oxidation of both xenobiotic and endogenous compounds

What are the two major SNPs identified in CYP2C9 polymorphism?

CYP2C9*2 (decreases activity by 30%) and CYP2C9*3 (decreases activity by 90%)

Give an example of a drug that is metabolized by CYP2C9.

Warfarin

How does warfarin work as an anti-coagulant?

It inhibits vitamin K epoxide reductase complex 1 (VKORC1), reducing the synthesis of thrombocytes

What is the consequence of CYP2C9 polymorphism for warfarin metabolism?

Reduced metabolism and lower warfarin doses required

What is the purpose of the ABCB1 transporter (P-gp)?

To remove drugs from cells and tissues

Where is P-gp expressed in the body?

Intestine, kidney, liver, blood-brain barrier, spinal cord, testes, placenta

How does P-gp affect the bioavailability of drugs in the intestine?

Lower intestinal P-gp increases the bioavailability of drugs

What are the consequences of ABCB1 polymorphisms for drug transportation?

Change in amino acid sequence and decreased expression of ABCB1

Give an example of a drug whose efficiency is affected by ABCB1 polymorphism.

Simvastatin (a lipid-lowering drug)

What are the different types of SLC transporters?

OATs (organic anion transporter), OATPs (organic anion transporting polypeptides), OCTs (organic cation transporter), PepTs (peptide transport proteins)

Where are SLC transporters expressed in the body?

Liver, kidney, brain, intestine

What is the function of the ADRB2 receptor?

Mediate bronchodilation, ventilation, and lipid metabolism

Give an example of a drug that targets the ADRB2 receptor.

Beta-agonists for asthma treatment

What are the common polymorphisms in the ADRB2 receptor?

Arg16Gly, Gln27Glu, Thr164Ile

What is the effect of the Ser49 and Arg389 polymorphisms in the ADRB1 receptor?

Enhanced receptor activity and increased response to beta blockers

How does the length of the serotonin transporter protein (SERT) allele affect drug response?

Longer alleles have a greater drug response than shorter alleles