PGX pf Drug Metabolizing Enzymes and Transporters

Question 1

Polymorphism effects (2)
PD vs PK

Answer 1

PK: ADME
PD: receptors, ion channels, enzymes, immune systems

no/little drug response: too quick drug metabolism, ADR
increased drug response: too slow metabolism, excessively high drug levels at usual dosage, high risk of ADRs

Question 2

PD
Metabolizing Enyzmes
2 phases

Answer 2

Phase 1: introducing an active FG that increases water solubility (oxidation or hydrolysis)
Phase 2: conjugation to increase water solubility or inactivates or detoxifies

CYP450 most common phase I enzymes

Question 3

which enzymes have high polymorphisms

Answer 3

2D6, 2C19, 2C9 have high polymorphisms

Question 4

alleles for different types of metabolizers

Answer 4

Extensive metabolizer = normal, wild-type
Intermediate = slower than normal, polymorphic, partial reduced function (give same dose and monitor usually)
Poor metabolizer = polymorphic allele, total loss of function or very low (change drug or increase dose)

Question 5

What would happen if a prodrug is given to a poor metabolizer?

what about a normal drug?

Answer 5

• Prodrug activated inside of body,
• Poor metabolizer - decreased active form of drug inside the body
• Will see lower therapeutic effects, low conc. of active entity
• Can increase dose or change the therapy not dependent on that enzyme
• Rarely get side effects with high prodrug concentration
• normal drug would have more active drug in blood stream as it is not metabolized

Question 6

Describe the phenotypes based on the alleles of CYP2D6

Answer 6

• over 70 variant alleles (old stat)

2 inactive/null alleles = poor metabolizer

Decreased functional alleles = IM

2 Fully functional alleles = EM

Greater than 2 fully functional allele = ultrarapid metabolizer

Question 7

How are the CYP 2D6 allele functionality effects determined?

Answer 7

• genotyping and phenotyping
• in phenotyping dextromethorphan which is a specific CYP2D6 probe drug is given
• relative ration b/w conc of probe drug (DM) and its metabolite (dextorphan DX) is obtained
• high DM: DX = poor metabolizers
• low DM:DX = extensive metabolizers

Functional normal = activity score of 1
Reduced function = 0.5
Non-functional = 0
score depends on guideline

refer to guidelines to make decisions

Question 8

CYP2Y19

5 types

Answer 8

NM
IM
PM
RM
UM
normal is *1/*1
clopidogrel is affected

Question 9

CYP2C9

Answer 9

*2, 3, 5, 6, 8, 11 alleles associated with reduced S-warfarin clearance

Question 10

Name 2 transporters

Answer 10

ATP-Binding Cassette (ABC) Family Transporters
Solute-Carrier Family Transporters (SLC)

both have many polymorphisms
- need to consider if it is efflux or influx transporter, does size or concentration matter, is it passive?

-transporters differ in diff locations (intestinal epiuthelia, hepatocytes, kidney proximal tubules, BBB)

Question 11

ABCB1 gene

what is it involved in?

Answer 11

• gene aka multidrug resistant 1 (MDR 1) encodes P-glycoproteins that is involved in cellular efflux of several chemotherapeutic agents and physiological metabolites

Question 12

ABC genes

Answer 12

ABCs have tissue locations, substrates, inhibitors, and inducers

Question 13

Polymorphism of ABCs

Answer 13

• increased activity of transporter
• loss in activity
• no change

Question 14

Solute-Carrier Familty Transporters (SLC)

types (3)

need to know drug to determine function depending on the alleles

example

Answer 14

• organic anionic transporters (OAT) - only carries anions
• organic anionic transporters polypeptides (OATP)
• organic cationic transporters (OCT)

SLCO1B1 function - affects simvastatin
polymorphism - reduced transporter functionality, more of it is in the blood concentration leading to side effects

Question 15

how to adjust therapy if there is induction of an enzyme?

Answer 15

increase dose to reach therapeutic effect

Question 16

how to adjust therapy if there is inhibition of an enzyme?

Answer 16

decrease dose to prevent ADR or change therapy