concepts in drug metabolism

Friday, June 13, 2008

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

1-Aromatic (benzene ring) → para hydroxylation.

(R is the rest of the molecule)

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 → oxidation of 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 in a second step)

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)

........R- NH2 → R-NO2 (nitro).

11-An OCH3 group R-OCH3 → R-OH (alcohol)+ HCHO

12-An (R-S-CH3) → removal of CH3 → R-SH + HCHO
..........the carbon removed should have H

..............→ 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-COOH (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 Acetyl group.

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

Good Luck

Lecture I in points

1. purpose of drug metabolism
*end pharmacologic activity.
*ends toxicity.
*increase polarity.
2.there are exceptions.
*bioactivation.
*active drug and metabolite.
*toxic metabolite.
3.Sites of metabolism.
*hepatic (major).
*extrahepatic(intestine, kdney, lungs etc..)
4-Metabolic pathways:
*Phase I (Functionalization) handle formation.
*Phase II (Conjugation).
5.Phase I
A-Oxidation reactions:
i-Catalyzed by Cytochrome P450
*Oxidation of aromatic moieties
....Arene oxide intermediate
.....gives para hydroxy metabolite
.....Major pathway.
.....oxidaiton of only one ring.
.....oxidaiton of electron rich ring.
*Oxidation of oliphins:
......Epoxide intermediate (stable and toxic).
.....Gives diol metabolite.
*Oxidation of benzylic carbon:
........Alcohol metabolite.
........Further oxidized.
* Oxidation of allylic carbon:
*Oxidation of carbon alpha to carbonyl an imine:
........secondary alcohol metabolite.
*Oxidation of aliphatic and alicyclic carbon:
.......Oxidation of ω and ω -1 carbon.

Lecture II in points

*Oxidation of C-heteroatom systems:
.Cytochrome P450
.Two types of oxidation
.oxidation of α carbon or the heteroatom.
........I-Oxidation of C-N system
A-Oxidation of the carbon α-to the heteroatom.
.Carbinolamine unstable intermediate.
.Elemination of an alkyl group (N-dealkylation).
.Aldehyde metabolite+amine moiety.
.Smaller alkyl gps eleminated faster.
.α H is a must (an exception is mentioned).
.Removal of the first alkyl in tertiary amines group is faster.
.dealkylation of T- amine → secondary amine metabolite.
.oxidation C α to N in alicyclic ring → lacatam.
.dealkylation of T-amine is faster than secondary.
.Dealkylation of S-amine → primary amine metabolite and aldehyde moiety or aldehyde metabolite and amine moiety.
.Dealkylation of P-amine → aldehyde metabolite and amonia.
B-Oxidation of the Nitrogen:
.T-amines →Noxide.
.S-amines →hydroxylamine →nitrone.
.P-amine →hydroxylamine →nitorso →nitro.
..........Aromatic amines and heterocycles.
.Oxidation of Nitrogen is the same as aliphatic amines.
.Dealkylation of T- and S-aromatic amines is simlilar to aliphatic.
.P-aromatic amine no dealkylation oonly N oxidation.

Lecture III in points

.........Oxidation of Amides
.Oxidative Carbon-Nitrogen cleavage.
.product is amide and carbonyl moity.
.Oxidation of the Nitrogen gives Hydroxylamide.
.Oxidation of aromatic amides may give toxic metabolite.
.Protection in small dose By GSH
.........II-Oxidaiton of C-O system
.Attack only on α-Carbon.
.α-H must be present.
.Oxidative Dealkylation.
.Hemiacetal or hemiketal intermediate.
.produc is alcohol metabolite and carbonyl miety.
.........III-Oxidation of C-S System.
a-Oxidation of α-carbon.
.leading to formation of thiole and carbonyl metabolite.
.α-H must be present.
S-dealkylation.
b-Desulfuration
.Replacement of C=S with C=O by oxidative reaction.
.Cytochrome P450.
c-Oxidation of Sulfur atom
.One Oxygen atom gives Sulfoxide
.Two oxygen atome gives Sulfone metabolite.
........Oxidation of alcohols and aldehyde
.Bothe catalyzed by alcohol dehydrogenase.
.non-micrisomal enzyme.
.primary alcohol gives aldehyde.
.Secondary alcohol gives keton.
............Reductive Reactions
i-Reduction of aldehydes and ketones.
.Aldehydes more readily oxidized to acids.
.Ketones give secondry alcohol (assymetric center).
.Catalized by aldoketoreductases (alcoholdehydrogenas).
ii-Reduction of azo and nitro compounds:
.Gives primary amines.
.eg.reduction of prontosil to sulfanilamide.
.aromatic nitro go through reverse of oxidation reaction.
iii-Miscellaneous reductios:
.Reduction of N-oxides to tertiary amnies.
Reduction of sulfoxides to SH.
..............Hydrolytic reactions
i-Hydrolysis of esters Fast reaction.
.Catalyzed by estrases.
.Products are alcohol and acid
ii-Hydrolysis of amides slower
.amidases
.product is amine and acid.

Lecture IV in points

..........Phase II (Conjugation)
...........Synthetic
.Conjugates functional group to indogenous compound
.Product not pharmacologically active.
.Wter soluble (ecept acetyl and methyl conjugates).
.Non-toxic (exception).
.Requires energy.
.Requires activation of either drug or the conjugating agent.
...............I-Glucuronic Acid conjugation
.Most common.
1-Most functional groups react with glucuronica acid.
2-product is very soluble .
3-Glucuronic acid (from glucose).
.Glucoronic acid is activated to (UDPG).
.Glucuronyl-transeferase caltalizes the transfer.
.product is B-glucuronide.
..............II-Sulfate conjugation
.Sulfate is limited in body.
.for indogenous compounds.
.Mostly phenols.
.Some sulfate conjugates are toxic.
.Sulfate metabolite is very water soluble.
.Sulfate is activated to PAPS.
.Sulfotransferase catalyzes transfer.
.........III-Conjugation with Glycine and glutamine
.Amino acids availability limited.
.Mainly conjugation of acids.
.The acid drug activated to Acyl COA
.N-acyl transferase catalyzes the transfer.
........IV-GLutatione or mercapturic acid conjugation
.Protects the body from electrphils.
.Composed of Glutamine ,cystine and glycine.
Reacts with SH of cystine.
.No initial activation.
.Substrate binds to SH of cystine covalently.
.Sequential break of glutemine and glycine and leaves S- substituted cystine.
.N-acetylation of the product gives mercapturic acid which is eleminated.
..................V-Acetylation.
.Mainly for primary aromatic amines among others.
Product is inactive but low water soluble.
.Active form is Acetyl COA.
.Acetyl transferase catalyzes the transfer.
...............VII-Methylation
.Ends pharmacologic activity but doesnot increase water solubility.
.Also in biosynthesis of indogenous compounds.
Active form is SAM.
.Methyl transferase catalyzes the transfer.
.......Factors affecting drug metabolism
1-Age ( the infants and the elderly).
2-Genetic or Heriditary factor.
Bimodal distribution of acetylators.
3-Species difference.
4-Sex differences.
5-Enzyme induction.
6-enzyme inhibition.
7-Miscellaneous factors