PGx and PK

Question 1

Absorption of drug

Answer 1

related to route of drug administration (have to think about first-pass effect)

Question 2

Distribution

Answer 2

have to think about whether you have a wide enough distribution for drug to reach target site (have to think about both parent drug and metabolite)

Question 3

4 types of disease status in therapy

Answer 3

1. Pt responds to drug w/ no toxicity (ideal)
2. Pt responds to drug with toxicity
3. Pt does not respond to drug w/ no toxicity
4. Pt does not respond to drug with toxicity

Question 4

Valid genomic biomarkers/ targeted therapy

Answer 4

specific clinical tests (genomic markers) that can be used in improving efficacy and/or reducing/preventing side effects

Question 5

Major source for genetic variability in oral drugs

Answer 5

Bioavailability of drugs
Also have to think about drug uptake
Also have to think about first-pass metabolism

Question 6

Drug distribution

Answer 6

mainly assoc with plasma protein binding (albumin & alpha-1-acid glycoprotein)
ORM2A= most important glycoprotein assoc with binding of basic drugs

Question 7

Drug elimination/ transport primary transporter

Answer 7

Assoc with P-glycoprotein (P-GP)
has to do with anticancer drug resistance (multiple drug resistance MDR)
transports a wide variety of drugs
used as a biomarker and target in anticancer pts

Question 8

Other transport mechanisms involved with elimination/ transport

Answer 8

MRP family= multi-drug resistant protein (often transport acids and GSH conjugated drugs)
OAT family= organic acid transporter
OCT family= organic cation transporter
OATP family= organic anion transporting polypeptide (transports many lipophilic agents)

Question 9

Phase I Drug Metabolism

Answer 9

• Try to convert water insoluble drugs to water soluble drugs (Once it is water soluble, it can be excreted)
Generally P450 “oxidizes” drugs by putting on a polar OH group (also can do dealkylation, deamination, N-oxidation)
Can also prepare drugs for Phase II metabolism

Question 10

What’s the gene that encodes P450?

Answer 10

CYP
4 classes of CYP’s (CYP1-3 are important for drugs, CYP4 not important as much since largely involved in fatty acid metabolism)

Question 11

CYP3A4

Answer 11

• largest form expressed by the liver (MORE THAN HALF of the drugs we use are metabolized by it!)
• induction and inhibition
• variants reported in several studies
• Enzyme is so abundant that even if you have a deficiency/ prob with activity, it won’t usually be affected much (Not a super severe clinical consequence unless it is EXTREMELY low)

Question 12

CYP2C9

Answer 12

20% of total liver CYP (2nd most abundant after 3A4)
2 major variants studied: (Caucasians have most)
1. CYP2C92= Cys instead of Arg
2. CYP2C93= Leu instead of Ile; pronounced reduction in catalytic activity
*Impact on therapy is linked to type of mutation
Heterozygotes= minimal impact
Homozygotes= serious prob; very poor activity

Question 13

CYP2C19

Answer 13

Variants mostly seen in Blacks and Chinese (Chinese most)
Poor metabolizers are predisposed to ADRs of mephenytoin – sedation
Impact= not very large since most drugs can be metabolized with another P450

Question 14

CYP2D6

Answer 14

many many variants (highly polymorphic)
mostly in whites
poor metabolism trait is autosomal recessive= only seen in homozygotes
4 groups of metabolizers = ultrarapid, intermediate, efficient, poor metabolizers

Question 15

CYP2D6 polymorphism

Answer 15

distribution shows enzyme activity –> enzyme activity linked to drug metabolism –> drug metabolism linked to clinical dose

Question 16

Phase II Drug Metabolism

Answer 16

involves addition of a polar group to the drug or its metabolites to facilitate elimination of drug metabolite
Usually polar group (Phase II) will convert drug to inactive form (Whereas with Phase I it could be converted to inactive or active form)

Question 17

Glucuronyl transferase (UGT)

Answer 17

transfers glucuronate group to drug in Phase II, conjugates bilirubin for excretion
Includes 2 families= UGT1 and UGT2
APAP and NSAIDs use it (so deficiency can lead to APAP sensitivity)
has 31 ID’ed genetic variants
Gilbert’s syndrome= UGT1A1 deficiency, compromised bilirubin excretion

Question 18

Glutathione-S-transferase (GST)

Answer 18

form thioether linkage to conjugate drugs
highly expressed in liver
multiple polymorphisms in humans: GSTM10 (no enzyme/ gene deletion); GSTP1 (involves AA 104 and 113 that have 15 fold catalytic activity toward anticancer drug)
Almost half caucasions and more than half chinese have GSTM10

Question 19

N-acetyl transferase (NAT)

Answer 19

acetylates N-aromatic amines
Two genes: NAT1 and NAT2
>20 polymorphisms
rapid acetylator= prob wildtype
affect sensitivity/ ADRs of drugs metabolized by this pathway = Isoniazid (neuropathy and hepatotoxicity), sulphonamide hypersensitivity, anofamide myelotoxicity

Question 20

Isoniazid- phenytoin interaction

Answer 20

due to NAT

slow acetylators of isoniazid show higher conc that inhibit CYP to where the phenytoin conc also increases –> toxicity

Question 21

UGT1A1 variants

Answer 21

increased susceptibility to toxicity in chemo agents

Question 22

Poor metabolizer with compromised liver function

Answer 22

• reduced first-pass
• increased oral bioavailability
• prolonged half life
• elevated plasma conc and toxicity
• possible decreased metabolism of other drugs

Question 23

Ultra-rapid metabolizer with highly increased liver elimination enzyme

Answer 23

• increased first-pass
• decreased oral bioavailability
• greatly increased metabolic clearance
• decreased plasma conc and decreased toxicity
• increased level of metabolites