Things to remember when applying to drugs

Phase I

*Cytochrome P450 looks for sites most electron rich and least sterically hindered
So aromatic rings with electron withdrawing groups (Halogens, Nitro, carboxylic acid etc..) are not oxidized.

*The same drug can be oxidized at different sites.

so when looking at a drug we look for
(R is the rest of the molecule)

1-Aromatic (benzene ring) → para hydroxylation
2-Olifin (double bond) → diol

3- Methyl group attached to benzene (benzylic carbon) → alcohol
4-Methyl group attached to C=C (allylic carbon) → alcohol
5-Carbon next to carbonyl and imin (benzodiazepine) → secondary alcohol
6-long chain → ω (terminal) carbon or ω -1 (carbon before the terminal) → alcohol
7-Alicyclic (saturated ring) → alcohol on para position.

8-Tertiary or secondary aliphatic amine → removal of a methyl group to give amine

.....(make sure to remove the smaller group)

.....(called oxidative dealkylation)

.....(make sure the alkyl group removed has H on it )

.....(if the other group is small will be removed too

9-Tertiary nitrogen (nitrogen with no hydrogen on it) → N-oxide.

10-Primary amine (R-CH2-NH2) → NH3 (amonia) + R-CHO (carbonyl)

.......(oxidative deamination)

........(make sure the carbon next to N has H on it)

or

........ NH2 → NO2 (nitro). 11-An OCH3 group → OH +OCHO

12-An (R-S-CH3) → removal of CH3 → R-SH + HCHO

..........the carbon removed should have H

or

..............→ Oxidation of the sulfur → Sulfoxide or sulfone.

13-A Sulfur attached to a carbon with double bond C=S → C=O (oxidative desufuration)

14- R-CH2OH (alcohol) → R-CHO (aldehyde) → R-CH2CH2CH2COOH (acid)

15- R-COOCH2R' (ester) → RCOOH (acid)+ R'-CH2OH (alcohol)

16-R-HNCO-R' (amide) → R-NH2 (amine) + R-'COOH (acid)

*all the functional groups produced above (aromatic OH ; NH2 ; C=O ; COOH ; SO2 ; NO2 ; SH etc...) will be conjugated in phase II.

*If a drug has a functional group before metbolism e.g. OH or COOH or aromatic NH2 etc.. It can go directly to phase II and conjugates this functional group to a conjugating agent (mostly glucoronic acid)

*Aromatic amines are famous for conjugation to aAcetyl group.

Please apply all these rules to the drugs given in the lectures.

Good Luck