Drug Metabolism || Medicinal Chemistry ||PharmaEasyNotes ||Phase I - II ...

All the chemical substances that are not nutrients, which enter the body through

ingestion

inhalation or absorption

is called xenobiotics or exogenous compounds.

• Drugs are also xenobiotics under their lipophilicity. Water-soluble agents undergo renal excretion whereas lipid-soluble substances are passively reabsorbed from the renal tubule into the blood after glomerular filtration.
• This enzymatic biotransformation is known as drug metabolism. " Drug biotransformation is thus a detoxification process.

a) Sites of Bio-transformation

The Principle site of drug metabolism is not only the liver but also the kidney, lungs, and GI tract are also important sites.

When a drug is taken orally, it is usually absorbed through a mucous membrane of the small intestine or from the stomach.

Once out of GI tract it is carried by the bloodstream to the liver, where it is usually first metabolized.

Metabolism by the liver enzyme before the drug reaching the systemic circulation is called the presystemic first-pass effect, which may result incomplete deactivation of a drug to increase the oral bioavailability.

First pass effect can be avoided by changing the route of administration.

b) Pathways of Drug metabolism

Drug metabolism has been divided into two categories

Phase I and Phase II transformation

Phase I: They are enzyme biotransformation reaction, in which drug may undergo a wide variety of oxidation,

reduction

hydrolysis,

• resulting in introduction or unmasking of a functional group, which increases the polarity of the molecule and serves as a center for the second phase of metabolic reaction.
• It is also called a functionalization reaction.
• These transformations are also called synthetic reactions opposite to synthetic phase II reactions.

Phase II The original unaltered drug or polar metabolite is conjugated to glucuronic acid, sulfate, amino acid methyl group making the molecule more polar soluble, and therefore it is readily excreted.

General summary of Phase I and Phase II Metabolic pathway

Phase I Reactions

(I) Oxidative Reactions:

i) Oxidation of aromatic moieties

ii) Oxidation of olefins

iii) Oxidation at benzylic, allylic carbon atoms, and carbon atoms α to carbonyl and imines

iv) Oxidation at aliphatic and alicyclic carbon atoms

v) Oxidation involving carbon-heteroatom system

vi) Carbon- nitrogen systems (oxidative deamination, N-oxide formation, N-hydroxylation)

vii) Carbon-oxygen systems (O-dealkylation)

viii) Carbon- sulfur systems (S-dealkylation, S-oxidation, and desulfuration)

ix) Oxidation of alcohols and aldehydes

x) Other miscellaneous oxidative reactions