Nikolic Flashcards
Definition of drug metabolism. Goal.
the process of chemical alteration of drugs or any foreign substance termed xenobiotic inside a living organism. Turn lipophilic drugs into hydrophilic for excretion.
Name 3 inter-individual factors of metabolism
- species
- genetics
- sex
Name 6 intra-individual factors of metabolism
- age
- disease
- pregnancy
- stress
- nutrition
- enzyme induction/inhibition
Major phase I enzyme and major phase II enzyme?
CYP 450 and UDP glucuronyl transferase (for glucuronidation)
What kind of reaction is N-dealkylation?
Oxidation (Phase I)
What kind of reaction is demethylation?
Oxidation (Phase I)
Name a prodrug
Enalapril. The active metabolite is enalalprilate.
Where is CYP450 located in a cell?
It’s in the smooth endoplasmic reticulum
The E in CYP4502E1 is ___________.
Subfamily
The 6 in CYP4502D6 is _________.
isoform/member
Primary role of CYP450 is???
metabolism of endogenous compounds
Which families of CYP450 are mainly for drug metabolism?
Families 1, 2, 3
Families share _____% homology?
> 40% sequence homology
Subfamilies hsare _____% homology?
> 55% sequence homology
Which enzyme has no meaningful inducer?
2D6
Cigarette smoke induces what and the metabolism of what which causes what?
Induces enzyme 1A2, metabolism of Theophylline, causing asthma.
Inhibition is maximal when__________________.
inhibitor reaches steady state
Describe the active site of P450. “….in the middle of 4….”
Contains heme in hydrophobic pocket. Iron in the middle of 4 pyrrole rings. 5th ligand is thiolate anion from cysteine residue. 6th one occupied by the water molecule. ALL THE ACTIONS HAPPEN ON THE HEME.
P450 general interaction:
RH + O2 _ NADPH —–> ROH + NADP+ + H2O
What does the flavoprotein NADPH-cytochrome P450 reductase do?
It holds on the the H (electrons) from NADPH (which becomes NADP+) and give them to P450 enzyme one by one to let it form the H2O.
Describe the 2 step P450 reaction mech.
- hydrogen abstraction (that O from P450 taking that H from the drug RH to form OH on P450 itself)
- oxygen rebound (then giving the OH back to the R drug to form ROH)
In monosubstituted aliphatic rings, hydroxylation typically occurs at what 2 positions?
C3 and C4
N-dealkylation of benzphetamine
slide 78
What to do when you see alkene????
Epoxide. Very reactive electrophile. From very hydrophobic to hydrophilic. Make them ready for glucuronidation. EXAM QUESTION.
What’s an NIH shift?
It occurs in aromatic epoxides (arene oxide) in which an epoxide after nucleophile attach becomes a keto or enol.
Aromatic hydroxylation. What kind of groups would slow down aromatic hydroxylation and direct to meta position?
Electron withdrawing groups. COOH, NO2, +NR3, X
What kind of groups would speed up aromatic hydroxylation and which position(s) would it direct to?
Electron donating groups like OR, OH, NH2, R
For drugs with 2 aromatic rings, the more e–(rich/poor) one is usually hydroxylated
Rich, one next to electron donating groups like OH, NH2, OR, R
In MAO reactions, is the reactant H2O or O2? And what do you produce?
H2O; H2O2
What is the role of MAO?
To metabolize endogenous compounds like catecholamines (dopamine, epinephrine) into alcohols or aldehydes
What is disulfiram (Antabuse)?
It’s a treatment of alcoholism. Inhibits aldehyde dehydrogenase, leading to the accumulation of acetylaldehyde. This is what the Asian glow is=====>accumulation of acetyladehyde.
Amide hydrolysis is (faster/slower) than ester hydrolysis.
Slower.
