Tutorial Metabolism Phase-I

Tutorial_metabolism_phase-I

Since the body treat drugs as foreign compounds, what metabolism do to clear it from the body?
Do all drugs need to pass through phase-I metabolism? Which drugs can directly pass to phase-II?
Some drugs can be partially eliminated from the body without any metabolism. Why?
Drug interacts with metabolizing enzyme in a manner similar to drug-target interaction. However, the later interaction leads to no products. Is it the similarity of drug to enzyme substrate will determine whether this drug will be catalyzed to product or not?
Define drug metabolism
What are the main effects of drug metabolism
How the change in drug structure due to metabolism will affects solubility and activity? “which group is added on unmasked? Do some of these groups interact with receptor? What happen to interaction if they are lost?”
Do some drugs are excreted through bile acids? Why?
Can drug undergo phase-I after phase-II
Is it usual for a drug to stay pharmacologically active after phase-I?
Is it usual for a drug to stay pharmacologically active after phase-II?
What are the possible effects for metabolism on pharmacological activity of a drug?
Estrases can activate some prodrugs and can inactivate some drugs. Give one example for each case.
Does the metabolism of procaine by esterase lead to active metabolite?
Does the metabolism of hydrocortisone succinate lead to active metabolite?
regarding procainamide (Structure below) please find at least one possible sites for each of

a)Carbon oxidation

b)Oxidative N-dealkylation

c)Oxidative deamination

d)N-oxidation

e)Amide hydrolysis

Regarding propranolol metabolism please:

a)Indicate why oxidative dealkylation of terminal CH3 groups is a minor metabolite. “Is it due to steric hindrance?”

b)Why deamination is one of the major metabolites?
“is it easier than dealkylation for this molecule?”

c)Why oxidation is higher for the benzene ring
bears the oxygen? “Is this ring more electron
rich than the other ring?”

How codeine is activated to morphine which is then inactivated to nor-morphine?
How the aqueous solubility of hydrocortisone is increased by prodrug design? How the prodrug is activated to drug inside human body?
How the anti-nausea agent of thalidomide results in toxicity?
What phase-I reactions do to drug molecule?
What phase-II reactions do to drug molecule?
What are the main reactions involved in phase-I?
What are the main reactions involved in phase-II?
Mention 5 differences between products of phase-I and phase-II reactions regarding: m.wt, pharmacological activity, toxicity.
Why metabolites of phase-II cannot undergo phase-I reactions?
Why some drugs are highly metabolized by some enzymes and less metabolized by others.
Mention how the difference in dissociation constant for drug-enzyme interaction can affects the degree of metabolism.
How a drug can give different metabolites by metabolism with a single enzyme?
Does the orientation of drug binding to enzyme active site affects the type of metabolite being produced?
For CYP2C9 enzyme, what are the family, subfamily and member number?
If a cytochrome P-450 enzyme is a member 6 form family 2 and subfamily D. how you can write the abbreviated enzyme name?
Why CYP-450 enzymes need NADPH-dependent reductase?
How the oxygen atom can be activated inside CYP-450 enzyme? “is Fe+2 undergoes oxidation and give electron to oxygen?”
What are the three important needs for a carbon atom to undergo oxidative reaction?
Which of the two is the major metabolite for diazepam? Why?

Arene can be oxidized to arene oxide by CYP-450 enzymes. What are the possible fates (products) of arene oxide and which of the products are toxic and which are safe?

Why polychlorinated biphenyls are more toxic than non-chlorinated biphenyls?

Why polychlorinated biphenyls cannot be oxidized while benzo[alpha]pyrenes can be oxidized?
Why polychlorinated biphenyls (which cannot be oxidized) and benzo[alpha]pyrenes (which can be oxidized) are both toxic?
The succinic acid is usually used as polar molecule added to drug to increase drug polarity. Through which kind of bonds the succinic acid is connected to drug? Which metabolizing enzyme can release succinic acid from the drug?
Give two examples for drugs that can give toxic metabolites.
Why epoxide are less toxic than arene oxide metabolites?
How the metabolism of diamorphine produce active metabolites?

What are the most possible site for oxidation of the following compound?

Why the oxidation of alefininc carbon of aclofenac is easier than on aromatic carbon
Mention and point to four different oxidation sites for imipramine

A)Can be at aromatic ring, benzylic carbon, oxidative
dealkylation, and oxidative deamination

For the following compound, please point to the best site for oxidative metabolism.
“ is it on the terminal carbon close to the olefinic double bond?”.

regarding the next structure, mention whether the following metabolic reactions are possible and- if yes- what is the metabolite for each reaction

a)Oxidative deamination

b)Oxidative dealkylation

Mention two enzymes involved in phase-I metabolism and
another two for phase-II.
Why the oxidation of acetohexamide produce one major metabolite of 4-hydroxy derivative?

Which of the oxidative metabolites the following molecule can produce?

Draw the mechanism of N-dealkylation which involves the formation of carbinolamine intermediate.

Regarding the structure below, which of the two hydroxyl groups are more easily undergoesmetabolic oxidation? Why?

Chloramphenicol has been reported to cause grey baby syndrome in neonates after metabolism. Up to your knowledge, what is the reason behind this toxic effect?

Describe how the modification of ester bond into amide bond can increase the bond strength and reduce the metabolism.
Why the oxidation of amine and reduction of nitro group lead to toxic metabolites?

The mechanism of oxidative N-dealkylation of amphetamine is taking place through carbinolamine intermediate as below .