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Drug Metabolizing Enzymes, Transporters, and Drug Receptors II- Pathak

Terms in this set (30)

Where does metabolism (pharmacokinetics) take place?
In the liver, through hepatic enzymes
Describe the first-pas effect or pre-systemic metabolism.
Drug is metabolized at specific spot which results in reduced concentration in systemic circulation
What vein takes blood directly from the gut to the liver, and what vein returns blood black to the heart (system circulation).
Portal vein; Hepatic vein
What are the three drug metabolism pathways, and is it true that they only occur sequentially?
Phase I, II, III; they can occur simultaneously or sequentially
What kind of metabolite does each phase yield?
1. Phase I: Yields polar, water-soluble, metabolite that is often active

2. Phase II: Yields large polar, water-soluble, inactive metabolite
Tell whether metabolites are excreted from each phase (I,II,II) or not.
Phase I- Can't be excreted
Phase II- Excreted
Phase III- Can undergo more excretion
What reactions are involved phase I and II?
Phase I:
-Oxidation with cytochrome P450 or CYP (Common)
- Reduction
-Hydrolysis

Phase II:
-Glucuronidation (common)
-Methylation
-Acetylation
-Conjugation with glutathione
-Conjugation with amino acids
In phase I, products can also become what for phase II?
Substrates
What are the phase III mediators superfamilies?
1. ATP-binding cassette (ABC)
2. Solute Carrier (SLC) Transporters
When conjugated drugs are further processed in phase III, they are pumped out of the cells by:
Efflux transporters
List in the correct order the phase concept of drug metabolism.
1. Drug enters
2. Metabolism
3. Phase I: Functionalisation
4. Phase II: Conjugation
5. Phase III: Transport
6. Urinary or Biliary excretion
Cytochrome P450 (CYP) is a major part of drug metabolism that is responsible for __% of drug metabolism.
93%
Label each as either normal, ultra metabolizer, or poor metabolizer:

1. CYP2D6L
2. CYP2D6
3. CYP2D64
1. Ultra metabolizer

2. Normal

3. Poor metabolizer
What does the 2D64 respresent in CYP2D64?
2- Family
D- Subfamily
6-Iso-enzyme
4- Allele
What is the main drug-binding proteins present during distribution (pharmacokinetics)?
Albumin
Distribution (pharmacokinetics) is when a drug is transported from the systemic circulation to target tissues and organs, but only ____ drugs can ___ diffuse to extravascular or tissue sites to exerts its effects.
Unbound; passively
List all Albumin SNPS and their functional effects.
c.437t>A; p.(Val146Glu): Decreased plasma half-life

c.725G>A; p.(Arg242His): Low warfarin binding (common in white people)

c.878A>G; p. (ASP293Gly): High prostaglandin binding

c.1011g>T; p. (Lys337ASN): Low drug binding
What are the various types of drug receptors in pharmacodynamics?
1. Cell surface receptors:
- Ion channels
- G-protein coupled receptors
- Tyrosine kinase receptors

2. Intracellular receptors:
- Steroid receptors
How are ion channels opened, and is the membrane more or less permeable to ions? Also, is it true that this process is not needed for nerve conductance activation?
Via the drug binding to the receptor; More; No, it is needed
Describe the functional states of the voltage-gated sodium channel:
At hyperpolarized membrane potentials, the channel is closed.
It briefly opens due to depolarization causing Na+ current then the channel converts to non-conducting inactivated state.
What gene codes for the alpha subunit of sodium channel?
SCN4A
Polymorphism of the sodium channel (SCN4A-rs2302237) is associated with what disorder?
Oxaliplatin-induced peripheral neuropathy (OPIN)
When a drug binds to the receptor, it causes a g protein-mediated reaction in the cell. When the g protein is activated, what is then generated after before cell signaling occurs?
The second messenger (cAMP)
A 32 base pair deletion polymorphism in what gene confers resistance to HIV-1 infection?
Chemokine receptor 5 (CCR5)
A SNP on what H-RAS position contributed to the risk of gastric cancer, and what geneotypes are associated with an increased risk of gastric cancer compared to __ genotype (in Chinese populations).
81 (T81C); TC and CC; TT (found in Chinese people)
Describe "Drug receptors: Receptor tyrosine Kinase".
Drugs binds to transmembrane receptor to signal a change inside cell
What does EGFR encode for, and a polymorphism where is associated with lung cancer progression?
Epidermal Growth Factor Receptor; At exon 20
What drug exhibits better prognosis in EGFR wild type (GG) patients than AG or AA patients?
Gefitinib
Drugs that can enter the cell can bind to intracellular hormone receptors, and the drug-bound hormone receptors moves to the nucleus to do what?
Activate transcription and translation of certain proteins
The ___ polymorphism in what gene is associated with female infertility?
Asn680Ser; Follicle-stimulating hormone receptor (FSHR)
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