PG&PK 3 Flashcards
Phase II
Addition of a polar group to the drug or it metabolite
Converts the drug to the inactivated form
Phase II reactions are?
Glucuronidation Sulfation Glutathione transferase AA conjugation Acetylation Bile acid conjugation
UGT1A1
Deficiency = Gilbert’s syndrome
UGT1A6
Conjugates acetaminophen
UDP Glucuronosyl Transferase
Two families
Helps bilirubin be excreted
What are used to find out about UGTs?
Different probes are used to find out pharmacogenomics variations among the UGTs
Glutathione-S-Transferase
Responsible for inactivation of metabolites
Highly expressed in liver
GSTM1*0
45-52% White
58% Asian
22% Nigerian
33% Indian
N-Acetyl Transferase
> 20 NAT2 polymorphism
Polymorphs can lead to slow acetylation
Wildtype form of NAT
Rapid acetylators
NAT affects?
Sensitivity and ADRs like isoniazide neuropathy or hepatotoxicity
What makes polymorphism clinically relevant?
- Elimination
- Polymorph that is heterozygote or homozygote
- Enzyme activity affect
- Are metabolites active and potent
- Utilization of other metabolizing enzymes
- Other factor involvement
- Dose adjustment needed?
What do poor metabolizers do?
- Reduce first pass
- Increased oral bioavailability
- Reduce clearance
- Prolong half life
Elevated parent drug conc
Increase effects and toxicity
Reduce metabolite level
Inhibit metabolism of other drugs
Ultrarapid Metabolizers cause?
- Enhanced first pass
- Decreased oral bioavailability
- Increased clearance
- Shortened half life
- Decreased parent drug conc
Homozygote Normal
Two working genes
100% activity
