Phase-1 and Phase-2 drug metabolism
Metabolism is a process which terminates the action of the drug and helps in its Excretion from the body.
Drug metabolism is the process which describes biotransformation of drugs or nonessential Exogenous compounds in body so that they can be easily eliminated.
Drug metabolism occur by 2 different ways
- PHASE 1 REACTIONS
- PHASE 2 REACTIONS
1.PHASE 1 REACTIONS
- Phase 1 reaction is a predominant pathway of bio transformation.
- It is also includes oxidation, hydroxylation, reduction and hydrolysis.
- OXIDATION: Cytochrome P-450 is the major enzyme which is involved in the oxidative drug
- Metabolism. CYP450 is called mixed function oxidase(MFO).
- CYP450 is a heme-protein located in the endoplasmic reticulum.
Oxidation of carbon-heteroatom system (N, O, S)
Oxidative drug metabolism divided into following:
Oxidation or hydroxylation of heteroatom e.g
N-Hydroxylation: non basic nitrogen, non basic aromatic amines and basic amine are Metabolized by N-hydroxylation.
N-Oxidation: Hepatic monooxygenase system(CYP-350 and microsomal Flavin Contain monooxygenase).
S-oxidation: sulfides are oxidized to sulfoxides and to sulfones, all are eliminated in urine.
N- Dealkylation: the dealkylation of secondary and tertiary amine to yield primary and secondary amines.
O-Dealkylation : in o-dealkylation there is formation of hemiacetal or hemiketal as an intermediate which undergoes cleavage to form alcohol as drug metabolite.
REDUCTION:
Liver microsomes contain enzyme system that catalyzes reduction of azo and nitro
Compounds into primary amines.
HYDROLYSIS:
Hydrolysis metabolism is common in drug having ester or amide functional group.
The enzyme present in plasma and various tissues which are helps to hydrolysis metabolism.
PHASE-2 REACTIONS:
- Phase-2 reactions are known as conjugations reactions.
- drugs molecule or xenobiotics are conjugated with the glucuronic acids, sulphate, And glycine etc…
- Its increases the water of drug and decrease enough lipid solubility to make urinary Elimination possible.
DIFFERENT PATHWAYS AS FLLOWS:
- Glucuronidation
- Glutathione conjugation
- Sulfate conjugation
- Methylation
- Acetylation
- Amino acids conjugation
1.GLUCURONIDATION:
- It is known as glucuronic acid conjugation reactions.
- Conjugation of metabolite or drug with active form of glucuronic acid, uridine Diphosphate glucuronic acid.
2.Glutathione conjugations: It is known as mercapturic acid. It is important in the elimination of polycyclic phenols and halides.
3.Sulphate conjugation: It is important in the metabolism of steroid hormone, catecholamine, neurotransmitters,
Thyroxine, bile acid and phenolic drugs. Drugs having hydroxyl groups phenol and aromatic amine are conjugate. it occurs by enzyme called sulphotransfase and coenzyme PAPS(phosphoadenosine phophosulphate).
4. Methylation: Most of the endogenous amines undergoes methylation and get metabolized. Enzyme called (SAM) S-adenosyl-methionine help in the drug metabolism. drugs like dopamine, norepinephrine morphine are metabolized.
5. Acetylation: vDrugs conjugates with acetyl COA. vIt occurs by enzyme N-acetyl transfrases which present in the liver, lungs and speen.
6.Amino acid conjugation: vIt is helpful in the elimination of the drug containing aromatic acids & aryl alkyl acids. vAmino acids conjugates with drug to form water soluble.
