Drug Metabolism

METABOLISM OR BIOTRANSFORMATION
The conversion from one chemical form of a substance to another.

The term metabolism is commonly used probably because products of drug transformation are called metabolites.

Metabolism is an essential pharmacokinetic process, which renders lipid soluble and non-polar compounds to water soluble and polar compounds so that they are excreted by various processes.
This is because only water-soluble substances undergo excretion, whereas lipid soluble substances are passively reabsorbed from renal or extra renal excretory sites into the blood by virtue of their lipophilicity.

Metabolism is a necessary biological process that limits the life of a substance in the body.

Biotransformation: It is a specific term used for chemical transformation of xenobiotics in the body/living organism.
a series of enzyme-catalyzed processes—that alters the physiochemical properties of foreign chemicals (drug/xenobiotics) from those that favor absorption across biological membranes (lipophilicity) to those favoring elimination in urine or bile (hydrophilicity )Metabolism : It is a general term used for chemical transformation of xenobiotics and endogenous nutrients (e.g., proteins, carbohydrates and fats) within or outside the body.

Xenobiotics : These are all chemical substances that are not nutrient for body (foreign to body) and which enter the body through ingestion, inhalation or dermal exposure.

They include :
drugs, industrial chemicals, pesticides, pollutants, plant and animal toxins, etc.

Functions of Biotransformation
It causes conversion of an active drug to inactive or less active metabolite(s) called as pharmacological inactivation.

It causes conversion of an active to more active metabolite(s) called as bioactivation or toxicological activation.

It causes conversion of an inactive to more active toxic metabolite(s) called as lethal synthesis It causes conversion of an inactive drug (pro-drug) to active metabolite(s) called as pharmacological activation

It causes conversion of an active drug to equally active metabolite(s) (no change in pharmacological activity)

It causes conversion of an active drug to active metabolite(s) having entirely different pharmacological activity (change in pharmacological activity)

Site/Organs of drug metabolism
The major site of drug metabolism is the liver (microsomal enzyme systems of hepatocytes)
Secondary organs of biotransformation
kidney (proximal tubule)
lungs (type II cells)
testes (Sertoli cells)
skin (epithelial cells); plasma. nervous tissue (brain); intestines
Liver
The primary site for metabolism of almost all drugs because it is relatively rich in a large variety of metabolising enzymes.

Metabolism by organs other than liver (called as extra-hepatic metabolism) is of lesser importance because lower level of metabolising enzymes is present in such tissues.

Within a given cell, most drug metabolising activity is found in the smooth endoplasmic reticulum and the cytosol.
Drug metabolism can also occur in mitochondria, nuclear envelope and plasma membrane.

A few drugs are also metabolised by non-enzymatic means called as non-enzymatic metabolism.

For example, atracurium, a neuromuscular blocking drug, is inactivated in plasma by spontaneous non-enzymatic degradation (Hoffman elimination) in addition to that by pseudocholinesterase enzyme.
ENDOPLASMIC RETICULUM (microsomes): the primary location for the metabolizingenzymes.
(a) Phase I: cytochrome P450, flavin-containing monooxygenase, aldehydeoxidase, carboxylesterase, epoxide hydrolase, prostaglandin synthase, esterase.
(b) Phase II uridine diphosphate-glucuronosyltransferase, glutathione S-transferase, amino acid conjugating enzymes.
CYTOSOL (the soluble fraction of the cytoplasm): many water-soluble enzymes.
(a) Phase I: alcohol dehydrogenase, aldehyde reductase, aldehyde dehydrogenase, epoxide hydrolase, esterase.
(b) Phase 11: sulfotransferase, glutathione S-transferase, N-acetyl transferase, catechol 0-methyl transferase, amino acid conjugating enzymes.

MITOCHONDRIA.
(a) Phase I: monoamine oxidase, aldehyde dehydrogenase, cytochrome P450.
(b) Phase II: N-acetyl transferase, amino acid conjugating enzymes.
LYSOSOMES. Phase I: peptidase.
NUCLEUS.
Phase II: uridine diphosphate-glucuronosyltransferase (nuclear membrane of enterocytes).
Drug Metabolising Enzymes
A number of enzymes in animals are capable of metabolising drugs. These enzymes are located mainly in the liver, but may also be present in other organs like lungs, kidneys, intestine, brain, plasma, etc.

Majority of drugs are acted upon by relatively non-specific enzymes, which are directed to types of molecules rather than to specific drugs.

The drug metabolising enzymes can be broadly divided into two groups: microsomal and non-microsomal enzymes.
Microsomal enzymes: The endoplasmic reticulum (especially smooth endoplasmic reticulum) of liver and other tissues contain a large variety of enzymes, together called microsomal enzymes

(microsomes are minute spherical vesicles derived from endoplasmic reticulum after disruption of cells by centrifugation, enzymes present in microsomes are called microsomal enzymes).

They catalyse glucuronide conjugation, most oxidative reactions, and some reductive and hydrolytic reactions.

The monooxygenases, glucuronyl transferase, etc are important microsomal enzymes.
Non-microsomal enzymes: Enzymes occurring in organelles/sites other than endoplasmic reticulum (microsomes) are called non-microsomal enzymes.

These are usually present in the cytoplasm, mitochondria, etc. and occur mainly in the liver, Gl tract, plasma and other tissues.

They are usually non-specific enzymes that catalyse few oxidative reactions, a number of reductive and hydrolytic reactions, and all conjugative reactions other than glucuronidation.

None of the non-microsomal enzymes involved in drug biotransformation is known to be inducible.
TYPES OF BIOTRANSFORMATION
Phase 1 reaction. (Non synthetic phase).
a change in drug molecule. generally results in the introduction of a functional group into molecules or the exposure of new functional groups of molecules
: Phase I (non-synthetic or non-conjugative phase) includes reactions which catalyse oxidation, reduction and hydrolysis of drugs.

In phase I reactions, small polar functional groups like-OH, -NH2. -SH, -COOH, etc. are either added or unmasked (if already present) on the lipid soluble drugs so that the resulting products may undergo phase II reactions.
result in activation, change or inactivation of drug.
Phase II reaction. (Synthetic phase)
Last step in detoxification reactions and almost always results in loss of biological activity of a compound.
May be preceded by one or more of phase one reaction
Involves conjugation of functional groups of molecules with hydrophilic endogenous substrates- formation of conjugates - is formed with (an endogenous substance such as carbohydrates and amino acids. )with drug or its metabolites formed in phase 1 reaction.
Involve attachment of small polar endogenous molecules like glucuronic acid, sulphate, methyl, amino acids, etc., to either unchanged drugs or phase I products.
Products called as 'conjugates' are water-soluble metabolites, which are readily excreted from the body.