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Pharmacogenetics Midterm > PGx and PK > Flashcards

Flashcards in PGx and PK Deck (23):

Absorption of drug

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



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)


4 types of disease status in therapy

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


Valid genomic biomarkers/ targeted therapy

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


Major source for genetic variability in oral drugs

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


Drug distribution

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


Drug elimination/ transport primary transporter

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


Other transport mechanisms involved with elimination/ transport

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)


Phase I Drug Metabolism

• 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


What's the gene that encodes P450?

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



*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)



*20% of total liver CYP (2nd most abundant after 3A4)
*2 major variants studied: (Caucasians have most)
1. CYP2C9*2= Cys instead of Arg
2. CYP2C9*3= 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



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



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


CYP2D6 polymorphism

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


Phase II Drug Metabolism

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)


Glucuronyl transferase (UGT)

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


Glutathione-S-transferase (GST)

form thioether linkage to conjugate drugs
highly expressed in liver
multiple polymorphisms in humans: GSTM1*0 (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 GSTM1*0


N-acetyl transferase (NAT)

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


Isoniazid- phenytoin interaction

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


UGT1A1 variants

increased susceptibility to toxicity in chemo agents


Poor metabolizer with compromised liver function

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


Ultra-rapid metabolizer with highly increased liver elimination enzyme

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