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Glossary of Med Chem: Drug Metabolism

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Define xenobiotics
Drugs and other substances foreign to the body
Where does metabolism of xenobiotics take place?
primarily in the hepatocytes of the liver (through the action of enzymes)
What is the major site of extrahepatic metabolism?
GUT

(kidney, lungs and skin are minor)
Where are most drugs metabolized?
Liver
Enzymes modify the parent structure to a more ___________ product.
water-soluble
Define metabolic pathways
Various routes that a drug can take on its way to being enzymatically INACTIVATED and EXCRETED
In a compound, how many phase I reactions can occur? Phase II reactions?
Phase I: One or more
Phase II: only ONE
What are the 2 main goals of metabolism?
-Increased water solubility
-Enhanced rate of elimination
What are the four possible effects on drug action?
-Inactivation
-Maintenance
-Enhancement
-Bioactivation (of prodrugs)
Explain first pass metabolism
Drugs given orally are metabolized extensively in the liver (hepatic-portal vein) before reaching the general circulation

**This leads to decreased bioavailability**
Explain prehepatic metabilism
Refers to drug metabolism conducted by enzymes in the gut (before it ever reaches the liver)
Name a classic inducer of CYP 450.
Phenobarbital (Barbiturates)

(inducers - over metabolize - less effect)
Name a classic inhibitor of CYP 450
Cimetidine

(inhibitors - less metabolizing - toxicity)
What happens when CYP 450 is induced?
The drug is over metabolized leading to enhanced elimination and less therapeutic effect
What happens when CYP 450 is inhibited?
It keeps the drug from metabolizing leading to less elimination and toxicity
What is a unique inhibitor of CYP 3A4?
Grapefruit juice
What are some factors that influence metabolism?
-age, gender, nutrition, disease, race/ethnicity
-enviornmental toxins
-drug/drug and drug/food interactions
What are the three types of Phase I reactions?
RHO

Reductions
Hydrolyses
Oxidations
What is another name for Phase II reactions?
Conjugation reactions
What is the main enzyme family in oxidations?
CYP450
What does the CYP450 system do?
chemically inserts a single oxygen atom into their substrates
CYP450 metabolism requires four things:
1. A heme protein
2. NADPH
3. Phosphatidylcholine
4. Molecular Oxygen
CYP450 is in a resting state when bound to _____ and in an active state when bound to _____.
Fe3+ (oxidized); Fe2+ (reduced)
What is the primary phase I reaction?
Oxidation

(then reductions then hydrolyses)
What is genetic polymorphism?
When a racial group does not metabolize drugs well

-poor metabolizers can lead to reduced therapeutic effect
-ultrafast metabolizers can lead to toxicity
Where does Hydroxylation take place?
Aromatic rings, non-aromatic rings and carbon chains
In phenyl rings where does hydroxylation take place?
Primarily at the Para-position (if it is not blocked by a substituent)

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