Biotransformation is the process by which lipid soluble drugs are converted to water soluble metabolites for excretion. The objectives are to inactivate drugs, enhance effects, or convert prodrugs to active drugs. The major sites are the liver, intestines, stomach, blood, brain, kidneys, and lungs. First pass metabolism occurs when orally administered drugs are absorbed and transported to the liver where they undergo extensive metabolism before reaching systemic circulation. Drug metabolism enzymes, especially cytochrome P450 enzymes in the liver, catalyze biotransformations through phase I reactions like oxidation and reduction and phase II conjugation reactions. Factors like age, weight, sex, genetics, disease processes, and drug interactions can impact an individual's

1. Biotransformation
 A process by which lipid soluble drugs are converted to
water soluble for their excretion
OBJECTIVES:
 To inactivate pharmacological effect
 To enhance pharmacological effect(diazepam to
oxazepam)
 To convert prodrugs into active drugs.
Aspirin to salicylic acid
Codeine to morphine

2. SITES
 Liver(morphine propenolol verapamil)
 Intestines e.g clonazepam
 Stomach(penicillin,insulin),
catecholamines
 Blood
 Brain
 Kidneys
 lungs

3. First Pass Metabolism
Definition:
After oral administration, certain drugs are absorbed
intact from small intestine and transported to liver via
portal circulation where they under go extensive
metabolism e.g morphine, verapamil, warfirin.
Significance:
Individuals whose liver functions are derranged doses
of these drugs should be adjusted accordingly.
Also in certain systemic diseases(CCF)dose need to be
adjusted.

4. Drug Metabolism Enzymes
Biotransformations in-vivo can occur by spontaneously,
non-catalyzed chemical reactions. However, most
transformations are catalyzed by certain cellular enzymes.
Location:
At sub-cellular level, they may be located in smooth
endoplasmic reticulum, mitrochondria, cytosols,
lysosomes.
Mixed Function Oxidases:
→ Located in SER and are responsible for oxidative drug
metabolism.
→ They require a reducing agent, NADPH and molecular
oxygen, of which oxygen atom appearing in the product
and the other in the form of water.

6. Human Liver P450 Enzymes
There are numerous P450 isoforms of which the
following are important:
CYP3A4 account for >50% of all prescribed
metabolism
P450 Isoform Percentage of human liver (%)
CYP1A2 15
CYP2A6 4
CYP2B6 1
CYP2C9 20
CYP2D6 5
CYP2E1 10
CYP3A4 30

7. REACTIONS
• Phase 1 (non-synthetic)
• Phase 2(synthetic)
Phase 1:
conversion of parent drug to more polar
metabolites(-OH,-NH2,-SH).
Phase 2:
An endogenous substate (glucoronic acid,
sulphuric acid amino acid,acetic acid)forms a
polar conjugate.

9. PHASE1
Oxidation:-
It is the most common reaction involve addition of oxygen
or removal of hydrogen from the drug
it is of following types:
 Hydroxylation of aromatic ring e.g phenytoin
 Aliphatic Hydroxylation e.g digitoxin
 N-dealkylation e.g morphine
 O-dealkylatin e.g
 N-oxidation e.g acetaminophen
 Suloxidation e.g cimetidine
 Deamination e.g amphetamine

10. PHASE1 (continued)
Reduction:-
Nitro benzene
Hydrolyses:-
Asters e.g Procaine
Amides e.g Procainamide

11. PHASE2
• Glucuronidation e.g acetoaminophen
• Acetylation e.g sulphonamides
• Conjugation e.g salicytic acid
• Sulfation e.g methyldopa
• Methylation e.g dopamine
• Water conjugation e.g carbamazepene

12. Drug elimination : Liver
Kidney
Urine
Drug molecule
Liver
More hydrophilic
metabolite
Conjugate
Bile
Feces
De-conjugation
and reuptake

13. Factors affecting Metabolism
• Related to Patient
• Age
• Weight
• Sex
• Racial difference
• Genetic factors
• Disease process
– Fever
– Thyroid hormone
– Liver disease

14. Factors affecting Metabolism
• Related to the drug
• Drug drug interactions
– Enzyme induction
– Enzyme inhibition

15. Enzyme Inducers
Certain P450 substrate drugs on repeated
administration induce P450 expression by
enhancing the rate of synthesis or reducing its
rate of degradation.
Rifampacin oral contraceptives
Carbamazepine clonazepam

16. Enzyme Inhibitors
There are certain drugs that inhibit cytochrome
P450 enzymes and therefore lead to decrease
metabolism of certain drugs.These can lead to
serious side effects e.g
Omeperazole:Warfirin