Points to remember

1-Metabolism is a Detoxification process .........(with exceptions)
2-Phase I Changes the structure by adding a functional group in order to
a-end the pharmacological activity............(with exceptions)
b-Increase polarity (convert it to water soluble).
c-Introduce Functional group to react in phase II

d-Liver is the main site of metabolism.

e-Kidney is the main site of excretion

Phase I metabolism

is

Microsomal Oxidation

(Introduction of one atom of Oxygen into the molecule (Cytochrome P450)).

*Introduction of a fumctional group

1-Carbon-Carb0n system

*Aromatic Oxidation (major ) → arene oxide → Para hydroxylation of only one electron rich (no electron withdraing groups) aromatic ring.
*Olifins → epoxide → Diols
*Benzylic cabon →→ alcohol
* allylic carbon →→ alcohol
* alicyclic →→ alcohol (para position)
*carbon next to carbonyl imin →→ alcohol
*long chain hydrocarbon → ω or ω -1 oxidation → alcohol
........The alcohol produced may be conjugated by phase II directly or
........if primary alcohols produced →→→ aldehyde then acid.
........if secondary alcohol is produced →→→ keton (revercible)

2-Oxidation of carbon - Heteroatom

Carbon-Nitrogen
......a-Oxidation of α carbon → Carbinolamine → Carbonyl (aldehyde or keton) + Amine(Oxidative N-dealkylation)

..................Small alkyl groups removed faster
...................α-carbon must have a hydrogen
...................first alkyl group removed faster.

b-Oxidation of the nitrogen
................Tertiary amine →→→ N-oxide (revesible)
................Secondary amine → hydroxylamine → nitrone
................Primary amine → hydroxylamine → nitroso → nitro

*Oxidation of aromatic amines and of amides will follow the same rules.
*The same rules are also true for Carbon - Oxygen system →→ carbonyl + alcohol.
*Carbon Sulfur System→→→
..........oxidation of α-carbon → SH and carbonyl
..........oxidation of S →→ S oxide →→ sulfone
...........Oxidative desulfuration (replace C =S with C=O).

Non- microsomal oxidation

Oxidation of alcohol to aldehydes and ketons by alcohol dehydrogenase (non microsomal),
Oxidation of aldehydes to acids by aldehyde dehydrogenase (non microsomal).

Reduction reactions

Ketones reduced (by alcohol dehydrogenase) →→ secondary alcohols (symetric center)

Reduction of nitro and azo compounds →→ amines (the opposit of oxidation reaction).

Hydrolysis reactions

*Hydrolysis of esters →→→ alcohol and acid (Very fast) (major)

*Hydrolysis of amides →→→ amine and acid (Slower)

Phase II (Conjugation)

*if the drug has a funcional group may go to phase tow directly.

*Requires activation (except glutatione conjugtion).

*Activation of the conjugating agent in

...........Glucuronic acid conjugaiotn (Major for all drugs) →active form UDPGA.

...........Sulfate (for alcohols)(minor) → active form PAPS

...........Methyl (catichols and phenols)(for indogenous compounds) → active form SAM

...........Acetyl (aromatic amines) → active form Acetyl COA

*activation of the the drug (aromatic acids)(Minor) → Active form of the drug Acyl COA

phase II (Conjugation produces non toxic metabolites (Except sulfate conjugation)

phase II increased solubility (except methylation and acetylation)

Glutatione conjugation is most important for protection againest electrophilic agents