9._metabolism_part2_1

5/25/2018 9._Metabolism_part2_1

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- C-N, C-O, and C-S oxidation involve two main types.

1- Hydroxylation of the -carbon atom directly attached toheteroatom, to produce unstable intermediate which decomposes bycleavage the C-X bond.

2- Hydroxylation of the heteroatom (N,S only) forming N-

hydroxyl, N-oxide, sulphoxide and sulphone.

Carbon-Heteroatom systems oxidation


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1- Hydroxylation of the -carbon atom directly attached to heteroatom,to produce unstable intermediate which decomposes by cleavage ofthe C-X bond.



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2- Hydroxylation of the heteroatom (N,S only) forming N-hydroxyl, N-oxide, sulphoxide and sulphone.

Oxime, nitrone, nitroso, imino



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- Nitrogen containing compounds are divided into three basic classes:

1- Aliphatic (1, 2, 3) and alicyclic (2, 3) amines

2- Aromatic and heterocyclic nitrogen compounds

3- Amides



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- Tertiary amines:

- Oxidative removal of alky group (oxidative N-dealkylation) by P-

450. Started by -carbon hydroxylation to form carbinolamineintermediate, then cleavage of C-N bond to secondary amine andcarbonyl moiety (Aldehyde or ketone).

C-N system oxidation


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- Small alky groups are normally removed quickly, and the first is

removed faster.


Methadone to pyrrolidine ring cyclization


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- Complete dealkylation reactions will lead to oxidation of primaryamine to carboxylic acid.

- t-butyl moiety is not possible to be removedbecause no alpha H tobe hydroxylated with the exception of t-butyl-norchlorcyclazine,which occur through oxidation of terminal CH3to carboxylic acidthen decarboxylated to produce H at alpha carbon.


Cl

N N

Cl

N N

OH

Cl

N N

COOHCl

N N


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- Tertiary alicyclic amines usually form Lactams(nicotine).



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- Secondary amines:Undergo oxidative N-dealkylation, oxidative deamination, and N-

oxidation reactions.- Oxidative N-Dealkylation:Carbinolamine pathway which produces

primary amine (the same as for tertiary amines).

- Examples:


propranolol methamphetamine

norketamine


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- Secondary amines:

- Oxidative Deamination:process by which a molecule loses the

primary amine group by the same carbinolamine intermediate.

- In general, the first step is N-dealkylation, then deamination

- There is an exception such as propranolol in which the oxidativedeamination can occur directly through the oxidation of the alpha-carbon of its secondary amine.



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- Metabolic oxidation reactions of Propranolol:



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- Norketamine does not undergo N-deamination. (why?)

- Norketamine can only undergo oxidative N-dealkylation



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- Also some alicyclic secondaryamines are transformed to theircorresponding lactams(phenmetrazine, methylphenidate).

- N-oxidationalso happens but to less extent to form N-hydroxylaminethat is prone to form nitronederivative



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- Primary amines:

- Primary aminesnormally undergo oxidative deamination or N-

oxidation. (endogenous compounds such as neurotransmittersoxidized via monoamine oxidase [MAOs]).



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- The possibility of alphacarbon oxidation depends on the availabilityof alphahydrogen (eg. Phentermine).


-Decarboxylationstep could happen first then deamination occur (methyldopa).amphetamine phentermine


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- Primary aliphatic amines which are not possible to be oxidized at

alpha position will beN

-hydroxylatedand further oxidationproduced nitrosoand nitrocompounds. (phenteramine, amantadine).



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- Primary aliphatic amines with alpha hydrogen can be N-

hydroxylated also.

- N-hydroxylationcould occur first then converted to imineby waterloss, then converted to oximewhich will be converted to ketone(amphetamine).



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Aromatic amines and heterocyclic Nitrogen compounds

- Tertiary and secondary aromatic amines are not common inmedicinal drugs while the primary amines are abundant(fromenzymatic reduction of aromatic nitro compounds, reductivecleavage of azo compounds and hydrolysis of aromatic amides).

- Tertiary aromatic amineswill undergo N-dealkylationand N-oxide

formation.



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- Secondary aminesundergo N-dealkylationandN-oxidationto giveN-hydroxyl amines which will oxidized again to give nitronederivatives, which they may hydrolyze to primary hydroxylamines.



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- Primary aromatic amines first produce hydroxyl derivative, then tonitroso.



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- Aromatic N-oxidationis considered a minorconstitute compared toN-acetylationand aromatic hydroxylation.

- Methemoglobinemiais a common side effect of aromatic amines(dapsone) when they are converted to N-hydroxyl derivatives. TheN-hydroxyl derivatives are able to oxidize the Fe+2to Fe+3inhemoglobin which will prevent oxygen transport (suffocation).



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- Aromatic amines are considered carcinogenic: activated by N-oxidation to make them highly electrophilic and alkylated by DNA,

RNA.


N

N

NH

N

N

N

OH

NN

N

OSO3-

NN

N+

nitrenium ionN

N

N

GLG


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- N-oxidationof N atoms inside heterocycle occur less common toproduce N-Oxide metabolite, (trimethoprim, cotinine and

metronidazole).



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- Oxidative C-N cleavage(- carbon hydroxylation) and N-hydroxylation reactions.

- Oxidative dealkylation occur through carbinolamideintermediate,unstable, fragmentation to form N-dealkylated product (Diazepam).

Amides


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Amides

Flurazepamchlorpropamide


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- Lactams, in the same way by forming carbinolamide that lead to C-Nbreakage(Cotinine).

Amides

Cotinine


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- Cyclophosphamide has many metabolites, see book page 73.

- Aromatic amides, minor extent, toxicological importance, 2-acetylaminoflourene (AFF) [N-oxidation, sulfonation, then nitrinum ionproduction].

Amides

Cyclophosphamide


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-Aromatic amides, minor extent, toxicological importance, 2-acetylaminoflourene (AAF) [N-oxidation, sulfonation, then nitrinum ion

production].

Amides


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- Acetaminophen:

Amides

HN CH3

O

OH

Renal excretion

HN CH3

O

ON-acetylamindoquinone

HN CH3

O

O

HN CH3

O

O

Glucuronide

SO3O-

Cause covalent binding with l ivercells, necrosis


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- Performed viamicrosomal mixed function oxidases.

- Oxidation involve -oxidation to form hemiacetalor hemiketal,

followed by C-O bond breakage (phenol, alcohol) and (ketone oraldehyde).

C-O System Oxidation

R1

H

OHOR2

R1 R3

OHOR2

Hemiacetal hemiketal

C O S O


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-Small alkyl groups removed first.


morphine

C O S t O id ti


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- Mescaline where the 3-O demethylation is favored.


C S S t O id ti


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- Undergo S-dealkylation, desulfuration, and S-Oxidation. The firsttwo involve C-S bond cleavage.

- S-dealkylationis proceeded in the same way as C-O and C-Ndealkylation by oxidizing the -carbon.

- Examples are 6-(methylthio)-purine produced 6-mercaptopurine.

C-S System Oxidation

N

N

N

H

N

S

N

N NH

N

SH

C S S t O id ti


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HN

NH

S

O

O

S COOH

CF3

S

C S S t O id ti


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- Desulfuration: Conversion of thiono (C=S) or (P=S) to (C=O) or P=Orespectively.

-Thiopental to pentobarbital

-and parathion to paraoxon.


C S S t O id ti


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- S-Oxidation reactions:

- Sulfide to sulfoxide to sulphone.


O id ti f Al h l d Ald h d


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- Alcohol is produced from different metabolic pathways such asoxidation of benzylic, allylic, alicyclic or aliphatic oxidation.

- If the OH is not conjugated, it will further oxidized.

- Primary alcohol and aldehydesgive facile oxidation to carboxylicacid.

- Less important, secondary alcohol to ketone, not that importantas it may be reduced again to alcohol as it is easier to beconjugated.

- The enzyme called alcohol dehydrogenaseperform reversiblereaction that converts alcohol to aldehyde and ketone, usingNAD+ as a coenzyme.

- Further oxidation of aldehyde to COOH, is done by aldehydeoxidaze and xanthine oxidize.

Oxidation of Alcohols and Aldehydes

Oth O id ti R ti


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- Oxidative aromatization, as in norgestrol.

Other Oxidation Reactions

Other O idation Reactions


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-Chloroform produce phosgene (hepato and nephrotoxicty).




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- Normally dehalogenation reactions produce toxic acylhalides.

9._metabolism_part2_1

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