DRUG

METABOLISM
(PHASE I)
Dr. Mohammad Javed Naim
Assistant professor
Pharmaceutical Chemistry-I
Semester I
Lecture 1
Date: 09 Oct 2023
Outline
◦ Drug metabolism & its types
◦ Biotransformation process
◦ Phase I metabolism
Objectives
◦ Our main aim to understand how drugs are getting metabolized though its various phases with
special emphasis on Phase I metabolism.
DRUG METABOLISM
Drug undergoes metabolism which leads to loss of its physiological activity and an increase in the

polarity and water solubility of the drug which results in more rapid elimination of the metabolites.

The metabolism of any drug is generally characterized by two phases of reaction:

❖Biotransformation (metabolic transformation)

❖Conjugation

Most drugs are metabolized at least to some extent by both phases of metabolism. E.g. Acetyl salicylic

acid whereas some drugs are considered chemically inert as they have been excreted unchanged i.e.

without any metabolic transformation. E.g. Barbitone

Biotransformation

◦ Biotransformation refers to the process by which lipophilic (fat-soluble), xenobiotic (foreign), or

endobiotic (endogenous) chemicals are converted in the body by enzymatic reactions to

products that are more hydrophilic (water-soluble).

◦ Sites:

Primary site: Liver

Other sites: Lungs, Kidney and Intestine

Process of Biotransformation
Advantages of biotransformation
❖Termination of drug action

❖Reduced lipophilicity

❖Renal or Biliary excretion

Phase I Metabolism (Non-synthetic phase)
❖It is called functionalization reaction.

❖Introduction of functional groups such as –OH, -NH2, -SH, -COOH, into the compound to produce

more water soluble compound.

Consists of the following reactions:

✓ Oxidation

✓ Reduction

✓ Hydrolysis
Oxidation reaction
❖Addition of Oxygen/Negatively charged radical or Removal of Hydrogen/Positively charged radical.

❖Oxidation is the main process of metabolism.

❖Produces unstable intermediates-Epoxides, Superoxides, Quinones.

❖There are basically 9 types of Oxidation reactions.

1. Oxidation at Nitrogen:

Examples: Chlorpheneramine

Dapsone
2. Oxidation at Sulphur:

Examples: Chlorpromazine

Chloramphenicol
3. Aliphatic Hydroxylation

Hydroxyl group added to drug

Examples: Ibuprofen

Tolbutamide
4. Aromatic Hydroxylation

Examples: Phenytoin

Propranolol
5. Dealkylation at Oxygen

Example: Phenacitin to Paracetamol

6. Dealkylation at Nitrogen atom

Example: Amitryptiline to Nortryptiline

7. Dealkylation at Sulphur

Example: Methylthiopurine to Mercaptopurine

8. Oxidative deamination

Example: Amphetamine
9. Desulfuration

Example: Parathion to Paraoxon

Reduction
❖Addition of Hydrogen/Positively charged radical or Removal of Oxygen/Negatively charged radical.
❖Reductive processes plays an important role in the metabolism of many compounds containing
carbonyl, nitro and azo compounds.
❖Bio-reduction of carbonyl compounds generated alcohol derivatives.
❖Nitro and azo reductions leads to amino derivatives.
❖The hydroxyl and amino moieties of the metabolites are much more susceptible to conjugation than the
functional groups of the parent compound.

❖Basically of two types: Microsomal reduction

Non-Microsomal reduction
❖Microsomal reduction by Mono-Oxygenase needs NADPH and cytochrome reductase.

✓ Nitro reduction
Example: Nitrazepam to 7-amino nitrazepam
Chloramphenicol to Aryl amine metabolite

✓ Keto reduction
Example: Cortisone to Hydrocortisone
✓ Azo reduction
Example: Prontosil to Sulphanilamide

❖Non-Microsomal reduction
Example: Chloral hydrate to trichloro ethanol
 Hydrolysis

❖The metabolism of ester and amide linkages in many drugs is catalyzed by hydrolytic enzymes

present in various and in plasma.

❖The metabolic products formed generally are polar and functionally more susceptible to

conjugation and excretion than the parent ester or amide drugs.

❖Hydrolysis is a major biotransformation pathway for drugs containing an ester functionality.

❖Hydrolysis of procaine
References

❖Ionescu, C., & Caira, M. R. (Eds.). (2005). Drug metabolism: current concepts.

❖Khan, M. F., & Philip, A. (Eds.). (2018). Fundamentals of medicinal chemistry and drug metabolism (Vol.

1). Bentham Science Publishers.

❖Abraham, D. J. (2006). Burger's medicinal chemistry and drug discovery.