L5 Drug Metabolism Flashcards
(44 cards)
What is the enzymatic catalyzed conversion of a drug or xenobiotic compound to their metabolites?
Metabolism
Drug metabolism primarily converts ___ drugs into more ___ metabolites.
Lipophilic; hydrophilic, polar
Most drugs are ___ and are readily reabsorbed in the ___.
Lipophilic; kidney
What are the two general consequences of drug metabolism?
- Increasing water solubility
2. Increased potential for excretion in urine or bile
What is the major site of drug metabolism and 5 other minor sites?
- Liver
- Intestine
- Skin
- Lung
- Kidney
- Brain
True or false - drug metabolism enzymes are expressed in about half of all cells.
False - they are expressed in essentially all cells
CYP450 and some metabolic enzymes are associated with the ___. Most other metabolic enzymes are present in the ___.
ER; cytoplasm
GI + Hepatic metabolism = ?
First pass Effect
What types of reactions occur in Phase I?
Oxidation, reduction, hydrolysis
What happens to the lipophilic drug in Phase I of metabolism?
Introduction/unmasking of a small function group that converts the drug into a more polar metabolite
What types of reactions occur in Phase II?
Conjugation reactions
What happens to the drug metabolite in Phase II?
Introduction of a large, highly polar endogenous functional group onto the drug metabolite; often occurs via the functional group created by Phase I reactions
What class of enzymes functions in 75% of all Phase I reactions?
CYP450
Where are CYP450 enzymes located?
Bound to the membrane of the ER
Why are CYP450 enzymes called “mixed function”?
The enzyme catalyzes a reaction in which two substrates are oxidized simultaneously (drug and the NADPH cofactor)
The most active enzymes for drug metabolism come from which three sub families?
CYP2C, 2D, and 3A
What are the four requirements for CYP450 reactions?
- Drug substrate
- Molecular oxygen
- NADPH
- NADPH-CYP450 oxidoreductase
True or false - there is one CYP enzyme for every structurally distinct chemical.
False - a single compound can be metabolized by multiple CYP450 enzymes and vice versa
What are the two major reason we need Phase II metabolism?
- Drug metabolite may still be active
2. Drug metabolite may not be sufficiently water soluble to allow for efficient excretion
Which Phase has a faster catalytic rate?
Phase II (slightly)
Where do Phase II reactions occur?
Cytoplasm (except glucuronidation)
What is required for a Phase II reaction?
- Drug substrate with a suitable functional group
- Specific enzyme
- Activated high energy co-factor or co-substrate
What is the most frequent and most important of the Phase II reactions?
Glucuronidation
What are inactive compounds that are metabolized in the body to their active forms?
Prodrugs
