Phase 1 and Phase 2 metabolism

1. PHARMACOLOGY
PHARMACOKINETICS: METABOLISM
Merlin Dinesh
S1, M. Sc CREM
CARE

2. Pharmacokinetics is the study of drug movement in, through and out of the body (ADME)
PHARMACOKINETICS

3. METABOLISM / BIOTRANSFORMATION
• the process of biochemical alteration of the drug in the body
• convert the nonpolar, lipid soluble drugs into more polar, water-soluble compounds
• So that the given drug is easily excreted
Sites of
Metabolism
Liver
Kidney
Intestine lungs
plasma
EFFECT OF
METABOLISM
DESCRIPTION EXAMPLE
Inactivation
Drugs/ active metabolite 
inactive compound
propranolol  4-hydroxyl
propranolol
Formation of active
metabolite
Active drug active metabolite
diazepam oxazepam
Activation of inactive
drug
Pro drugs active drugs Levodopa dopamine
Formation of toxic
metabolite
Drug active metabolite
(toxic in nature)
Paracetamol NAPQI
(hepatotoxicity)
NAPQI
N-acetyl-p-
benzoquinoneimine

5. METABOLIC ENZYMES:
Microsomal enzymes
• In liver
• CYP450
• CYP3A4-
Responsible for the
metabolism of more
than 50% of drug
Non microsomal
enzymes
• Cytoplasm &
mitochondria of
liver cell, plasma &
other tissues
• Ex. Esterase,
amidase

7. PHASE 1 / NON SYNTHETIC / FUNCTIONALISATION REACTION:
• convert the drug to a more polar metabolite
• Through oxidation, reduction or hydrolysis
OXIDATION:
• addition of oxygen or removal of hydrogen
• Most important
• Catalysed by mono oxygenases present in liver
• a system which includes cytochrome P450, NADPH and molecular oxygen
Types of oxidative reaction
Microsomal
oxidation
S-oxidation (sulfoxidation) Cimetidine cimetidine sulfoxide
N-oxidation Dapsone  hydroxylamine dapson
Dealkylation Codeine Morphine
Hydroxylation Phenytoin hydroxyphenytoin
Deamination Amphetamine Benzyl methyl ketone
Non microsomal
oxidation
Ethyl alcohol  CO2 + H2O

8. REDUCTION:
• Catalysed by microsomal or non-microsomal enzymes
HYDROLYSIS:
• cleavage of drug molecule by taking up a molecule of water
• occurs in liver, intestines, plasma and other tissues.
• choline esters, procaine, lidocaine, procainamide, aspirin, carbamazepine-epoxide, pethidine, oxytocin
Types of reductive reaction
Microsomal
reduction
Nitro reduction Chloramphenicol Arylamine
Keto reduction Cortisone  hydrocortisone
Non microsomal
reduction
Disulfiram and nitrites

9. CYCLISATION
• Formation of ring structure
• Ex. Proguanil to cycloguanil
DECYCLISATION
• Opening of ring structure
• Ex. Barbiturates, Phenytoin
Some other phase 1 reactions
If the metabolite of phase I reaction is not sufficiently polar to be excreted, it undergoes phase II reactions.

10. PHASE 2 / SYNTHETIC / CONJUGATION REACTION
• involve conjugation of the drug or its phase I metabolite with an endogenous substrate
• to form a polar highly ionized organic acid, which is easily excreted in urine or bile.
• have high energy requirement.
GLUCURONIDE CONJUGATION (GLUCORONIDATION):
• Conjugation with glucoronic acid
• increases the mol wt. of the drug which favours its excretion in bile.
• Most important
• Enzyme: UDP-glucuronosyl transferases (UGTs).
GTs are found in
most of the cells,
but found
abundantly in
Liver

11. ACETYL CONJUGATION (ACETYLATION):
• Non microsomal
• Enzyme: N-acetyl transferases (NATs)
• conjugated with the help of acetyl coenzyme-A
• Ex: sulfonamides
METHYL CONJUGATION (METHYLATION):
• Non microsomal
• Enzyme: Methyl transferases (MTs)
• conjugated with the help of methyl donors
• Amines and phenols
• Ex. Captopril, methyl dopa
SULPHATE CONJUGATION (SULFATION):
• Non microsomal
• Enzyme: Sulfo transferases (SULTs)
• Steroids, phenolic compounds
• Ex. Minoxidil

12. GLUTATHIONE CONJUGATION:
• Non microsomal
• Enzyme: glutathione-S-transferase (GSTs)
• epoxides and drugs with nitrate groups
• inactivates highly reactive intermediates formed during the metabolism of drugs
• Ex. Paracetamol
AMINOACID CONJUGATION:
• Non microsomal
• Conjugation with aminoacids
• Enzyme: N-acyl transferase
• Acidic drugs
GLYCINE CONJUGATION:
• Non microsomal
• Conjugation with glycines
• Ex. salicylates
Hoffman elimination
Some drugs undergo a unique type
of metabolism: they are
metabolised by spontaneous
degradation due to spontaneous
molecular rearrangement in
plasma and tissues
e.g. atracurium

13. FIRST PASS (PRESYSTEMIC) METABOLISM
• metabolism of a drug during its passage from the site of
absorption into the systemic circulation.
• All orally administered drugs are exposed to drug
metabolizing enzymes in the intestinal wall and liver
• can be avoided by administering the drug through
sublingual, transdermal or parenteral routes.
• The extent of FPM differs for different drugs
• an important determinant of oral bioavailability

14. Attributes of drugs with high first pass metabolism:
(a) Higher Oral dose.
(b) Individual variation in the oral dose (due to differences in the extent of FPM)
(c) Oral bioavailability is apparently increased in patients with severe liver disease.
(d) Oral bioavailability of a drug is increased if another drug competing with it in FPM is given
concurrently, e.g. chlorpromazine and propranolol

15. FACTORS AFFECTING DRUG METABOLISM:
• Chemical factors
• Enzyme induction
• Enzyme inhibition
• Biological factors
• Age
• Diet
• Sex difference
• Concomitant diseases
• Physiochemical properties of the drug
• Lipo philicity
• Hydro philicity
• Molecular weight

16. THANK YOU!