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Phases of Metabolism

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 CHEMICAL PATHWAYS FOR BIOTRANSFORMATION


The pathways of drug metabolism can divided in to:

  1. phase I
  2. phase II

Phase-I reactions

It includes oxidative, reductive and hydrolytic reactions.
In case of these type of reactions, the polar group is either introduced or unmasked, so the drug molecule becomes solublised and excreted.

It is asynthetic reaction because only small polar groups are introduced, not the whole complex is synthesized.
Polar groups like –OH, -COOH & -SH are added and leads to functionalization.

OXIDATIVE REACTION:

  • Introduction of group containing oxygen or oxygen and sometime removal of hydrogen is called as oxidative reaction.   
  • The metabolic oxidation occurring in the body is quite differ from chemical reaction, but relatively same.
  • Most occurring metabolic reaction in the body because of animal cells have easy availability of oxygen in normal condition. By oxidation only the cells forms energy in the body in form of ATP along the phosphorylation in ETC reaction.
  • Oxidation of the drug is catalysed by microsomal enzymes like CYPs, EMOs etc.
  • Some oxidation reactions are:

      Aromatic hydroxylation
      Aliphatic hydroxylation
      R-CH2-CH3  --> R-CH2-CH2-OH
      R-CH2-CH3 --> R-CHOH-CH2  
      Ex- digoxin, tolbutamide, cyclosporine, chloropropamide.


Epoxidation
R-CH=CH-R --> R-CH-O-CH-R
Ex- aldrin
 
Oxidative dealkylation
N- dealkylation: R-NH-CH3 --> R-NH2 + CH2O
Ex- morphine, caffeine, theophylline
O- dealkylation: ROCH3 --> R-OH +CH2O
Ex- codeine
S- dealkylation: RSCH3 --> RSH + CH2O
                       Ex- S-methylthiopurine.
 
 N- oxidation:
Primary amines: R-NH2 --> R-NH-OH ex- aniline
Secondary amines: R1-NH-R2 --> (R1 R2) –NH ex-acetaminophen
Tertiary amines: R1-NR2-R3 --> (R1 R2 R3) –N-->O ex-nicotine
 
 S- oxidation: (R1 R2) SH2 --> (R1 R2) S=O
 
Deamination: R-CH (NH2)-CH2 --> R-C (OH) -CH3 ex-diazepam
 
Desulphuration: (R1 R2) C=S --> (R1 R2) C=O ex- thiopental
 

REDUCTION:
Azo reduction: R-N=N-R’ --> R-NH-NH-R’ --> R-NH2 +R’-NH2
       Ex- prontosil, tatrazine.

Carbamoyl reduction: (R R’) C=O --> (R R’) CH-OH
Ex- naloxone (narcotic)

Nitro reduction: R-NO2 --> R-NO --> R-NHOH -->  R-NH2  
                                      Ex- chloramphenicol, nitrobenzene
 
HYDROLYSIS:
Ester: R-COO-R’ --> R-COOH + R’-OH
ex- procaine, succinylcholine (sk.muscle relaxant)

 Amide: R-CONH-R’ --> R-COOH + R’-NH2
Ex- procanamide, tidocaine, indomethacin.
 
Phase-II reaction

  • These reactions involve covalent attachment of small polar endogenous molecule like glucuronic acid, sulphate, glycine etc. to form highly water soluble substances. Thus, they are known as conjugation reaction.
  • The formed products have more molecular size. So, termed as synthetic reaction.



GLUCURONIC ACID CONJUGATION:
Also called as glucuronidation.
D-glucuronic acid is derived from the glucose, so it is readily available. The glucuronides can be generated by combination with alcohols, acids, amines etc. These enzymes associated with microsomal enzymes involved in oxidation and other. So the rapid excretion is carried out.
For, ex- conversion of phenytoin