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Pharm Exam 1
Set 4: Drug Metabolism
72
Pharmacology
Graduate
10/04/2011

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Term
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drug metabolism
Definition
the chemical alteration of xenobiotics within the body.

This may involve rearrangement of chemical bonds, incorporation or loss of atoms or molecules, or some combination.
Term
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xenobiotic
Definition
any compound normally foreign to living systems
Term
What 3 things can cause xenobiotic biotransformation?
Definition
Enzymatic processes
Non-enzymatic processes
Rearrangements
Term
What usually metabolizes drugs and/or xenobiotics that are analogues of physiological substances?
Definition
Specific enzymes normally responsibile for the disposition of these compounds.
Term
What can metabolize drugs and/or xenobiotics that have no edogenous counterparts?
Definition
Enzyme systems that exhibit broad substrate specificity
Term
What are the 3 reasons drug biotransformation is necessary?
Definition
1) Highly polar drugs are generally poorly absorbed & poorly transported across membranes.
2) Metabolism results in the transformation to more polar, hydrophilic compounds more readily excreted
3) Metabolic transformation facilitates elmination and may result in inactivation
Term
What is the principal organ of drug metabolism (tho nearly all tissues have some capacity)?
Definition
Liver
Term
What 4 "portals of entry" have significant capacity for drug metabolism?
Definition
Lung
GI
Skin
Nasal Mucosa
Term
How much capacity for xenobiotic metabolism do the kidneys have?
Definition
Significant as well.
Term
What 3 things contribute to the first pass effect restricting bioavailability of some oral drugs?
Definition
1) Oral drugs absorbed from sm. intestine are transported to the liver via the portal system and extensively metabolized prior to systemic circulation.
2) With some drugs, extensive metabolism also occurs in the intestinal mucosa
3) To a lesser extent, microorganisms can also metabolize drugs and contribute to the first pass effect.
Term
What are the 3 subcellular localizations of drug-metabolizing enzymes?
Definition
1) smooth ER
2) cytoplasm
3) mitochondria
Term
What occurs in Phase I metabolism?
Definition
Oxidation, Reduction, Hydrolysis => metabolite becomes more polar and possibily more readily excreted or ready for additional metabolism.
Term
What occurs in Phase II metabolism?
Definition
Conjugation of sm., endogenous substrate with functional groups already present on the drug or with those that are added/revealed by Phase I metabolism.
Term
What 2 compartments are P450s found in?
Definition
ER & Mitochondria
Term
Are P450s usually Phase I or Phase II metabolism enzymes?
Definition
Phase I
Term
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CYP450 system
Definition
a system where a flavoprotein is coupled to a hemoprotein terminal oxidase
Term
What is the flavoprotein in the CYP450 system?
Definition
NADPH CYP450 oxidoreductase
Term
What is the hemoprotein terminal oxidase in the CYP450 system?
Definition
CYP450
Term
What does the CYP450 system require as a source of reducing equivalents?
Definition
NADPH
Term
What type of environment is the CYP450 system in?
Definition
lipid environment. (therefore a membrane protein)
Term
How is CYP450 identified?
Definition
Distinct optical spectrum, due to thiol ligan to heme moiety
Term
How many genes, gene families, & subfamilies are there of CYP450?
Definition
>600 genes

18 human gene families

44 subfamilies
Term

CYP450 Catalytic Cycle

[image]

Definition

1) e-

2) O2

3) e-

4) H2O

5) [image]

Term
What is the nomenclature system regarding CYP450?
Definition
CYP#Letter#

CYP - CYP450
1st # - Gene Family
Letter - Gene Subfamily
2nd # - Individual Gene
Term
What is the nomenclature for a P450 pasudogene?
Definition
P450 name followed by a P
Term
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psaudogene
Definition
defective gene that doesn't produce a functional protein.
Term
How are psaudogenes formed?
Definition
As relics of gene duplications where one of the copies has degenerated and lost its function.
Term
Why are CYP450s capable of catalyzing a wide variety of monooxygenase reactions?
Definition
broad substrate specificity as individual proteins & as a super-family of enzymes.
Term
What are the 7 reactions cyp450 can do?
Definition
1) Dealkylation & Deamination
2) Dehalogenation
3) Desulfuration
4) Epoxidation
5) Hydroxylation
6) N-oxidation
7) Sulfur oxidation
Term
What 2 types of molecules can P450 hydroxylate?
Definition
Aliphatic (non-aromatic cyclic or acyclic)
Aromatic
Term
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Hydroxylation
Definition
RH -> ROH
Term
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epoxidation
Definition
[image]
Term
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dealkylation and deamination
Definition
removal of an HX group or an amino group (-NH2), where X is OR, NR2, SR
Term
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N-oxidation
Definition
A) Hydroxylamines R2NH -> R2N-OH B) N-oxides R2N -> R2N-O
Term
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Sulfur Oxidation
Definition
R2S -> R2S=O
Term
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Dehalogenation
Definition
RX -> ROH

X = F, Cl, Br, I, At, Uus
Term
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Desulfuration
Definition
RSH -> R-OH
Term
Which CYP familes are involved in drug metabolism?
Definition
CYP1 thru CYP 3
Term
Which CYP450 is involved in the biotransformation of almost all drugs? (also significant to poor bioavialability of drugs)
Definition
CYP3A4
Term
What metabolism are the other CYP450 families important for?
Definition
Endogenous compunds s.a. setroids & FA
Term
What additional proteins are needed by Flavin-Containing monooxygenases (FMOs)?
Definition
none
Term
What monooxygenase reactions do FMOs catalyze?
Definition
Same as CYP450
Term
What do FMOs require that CYP450s also require?
Definition
NADPH
Term
Where are FMOs localized in the cell?
Definition
ER
Term
What do FMOs prefer to oxidize over hydroxyl amines & N-oxides?
Definition
oxidation of secondary & tertiary amines & S-oxidation
Term
How many FMO gene products are there in mammals?
Definition
5
Term
How are CYP450s & FMOs similar?
Definition
1) ER localization
2) require NADPH
3) same overall rxn
4) broad substrate specificity
5) multigene family
Term
How are CYP450s & FMOs different?
Definition
1) P450s are also in mitochondria
2) FMOs have no accessory protein
3) FMOs prefer oxidation of secondary & tertiary amines vs. primary amines
4) FMO catalyzes S-oxidation
5) FMOs have of 5 genes while P450 has >600
6) Catalytic cycle differences in order
Term
What can FMOs do to thiols?
Definition
form a S-S bridge to connect them
Term
What does FMO do to tertiary amines?
Definition
RNH -> RN-OH
Term
What does FMO do to hydrazines?
Definition
forms 2 ractive intermediates
Term
What does FMO do to sulfides?
Definition
R2S -> R2S=O
Term

FMO Catalytic Cycle

[image]

Definition
1) NADPH + H+

2) O2 3) OX (X is the xenobiotic substrate) 4) NADP+

+ H2O
Term
What do the Phase II metabolism conjugation reactions involve?
Definition
High-energy intermediates & transferases
Term
How many steps are there to the glucuronidation pathway?
Definition
3
Term
What occurs in setps 1 & 2 in the glucuronidation pathway?
Definition
glucose activation/oxidation to UDPGA
Term
What occurs in step 3 of the glucuronidation pathway?
Definition
glucuronide formation
Term
What are the 4 glucuronides can be formed in glucuronidation pathway?
Definition
C-, O-, N-, S-glucuronidation
Term
How many steps are there in the Sulfate Conjugation Pathway?
Definition
3
Term
What occurs in steps 1 & 2 in the sulfate conjugation pathway?
Definition
sulfate activation of PAPS
Term
What occurs in step 3 of the sulfate conjugation pathway?
Definition
sulfate conjugation
Term
What are the 2 elements that can sufate conjugate?
Definition
N-, O-sulfation
Term
How many steps are there in the Glutathione Conjugation Pathway?
Definition
4
Term
What are the 4 steps in the GSH Conjugation Pathway?
Definition
1) GST (transferase)
2) GGT (gamma-glutamyl transpeptidase)
3) DP (dipeptidase)
4) NAT (n-acetyltransferase)
Term
What are 3 examples of gSh conjugation rxns?
Definition
CDNB (removes Cl)
DEM (removes double bond)
epoxides (open ring)

-adds an SG
Term
What 3 factors affect drug metabolism?
Definition
Induction
Inhibition
Genetic polymorphisms
Term
When might a person have increased de novo synthesis of CYP450?
Definition
exposure to certain drugs & environmental pollutants.
Term
What does increased CYP450 (induction) cause?
Definition
increased biotransformation & therefore decrease in the availability of drug, possibly increased toxicity (if metabolized active).
Term
How does CYP induction occur thru the pregnane X receptor (PXR)?
Definition
nuclear receptor-mediated signal transduction
Term
What occurs as a result to inhibition of drug biotransformation enzymes?
Definition
elevated levels of the parent drug, prolonged effects, increased toxicity
Term
Due to genetics, how are people classified based on their metabolic capacity?
Definition
extensive or poor
Term
Which metabolism category puts a patient at a higher risk for adverse effects?
Definition
poor
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