Elimination is the major process for removal of drugs from the body and termination of the drug action.
It causes irreversible loss of the drug from the body.
Eliminations occur two process:
Biotransformation (metabolism)
Excretion.
Biotransformation:
It is defined as the conversion of a chemical form of drug into another form using biological machinery.
The products of biotransformation may vary,
Some may retain activity.
Some effectless.
Some are even more effective.
Xenobiotics:
Any foregin chemical that is not a nutrient to the body and enters the body by ingestion, inhalation and absorption is called a xenobiotic.
Organs of Biotransformation:
Major site for biotransformation of xenobiotics is “Liver”.
Other organs where biotransformation takes place are as follows, (Descending order of extent),
Liver
Lungs
Kidneys
Intestine
Placenta
Skin.
Other organs are brain, muscles, spleen etc.
Drug metabolizing Enzymes:
The enzymes that cause biotransformation of the xenobiotics are different from the enzymes that cause metabolism of the nutrients, they are of following types.
Microsomal Enzymes:
The microsomal enzymes catalyze a majority of drug biotransformation reactions.
A microsome is a fragment of endoplasmic reticulum and attached ribosomes.
A large variety of microsomal enzymes catalyze a number of oxidative, reductive and hydrolytic and glucuronidation reactions.
Some important characteristics of the microsomal enzyme system are:
Lipoidal membrane-bound enzymes of the microsomes are essential for its selectivity towards lipid-soluble substrates.
The lipid-soluble substrate is biotransformed into a water soluble metabolite by the microsomal enzymes which can be easily excreted.
e.g. Cytochrome P450.
Non Microsomal Enzymes:
The non-microsomal enzymes include those that are present in soluble form in the cytoplasm and those attached to the mitochondria but not to endoplasmic reticulum.
These are also non-specific enzymes that catalyze few oxidative reactions, a number of reductive and hydrolytic reactions and conjugation reactions other than glucuronidation.
e.g. oxidases, peroxidases, dehydrogenases, esterases, etc.
CHEMICAL PATHWAYS OF DRUG BIOTRANSFORMATION
R.T.Williams, the leading pioneer in drug biotransformation research divided the pathways of drug metabolism reactions into two general categories
Phase I reactions,
Phase II reactions.
Phase I Reactions
These reactions generally precede phase II reactions and include oxidative, reductive and hydrolytic reactions.
Generally the polar groups are added to the xenobiotics.
Called “Asynthetic Reactions” as product is not totally altered.
The primary objectives phase I reactions are,
1. Increase in hydrophilicity
2. Reduction in stability
3. Facilitation of conjugation (Phase II).
Outcome of the Phase I reactions may be active, more active or inactive metabolites.
Phase II reactions.
Also called “Conjugation Reactions”.
Endogenous high molecular weight substances like glucuronic acid and glycine are attached to the xenobiotics to form high molecular weight conjugates hence called “Conjugation reactions”.
As new compounds are formed they are called “Synthetic Reactions”.
The outcome of the reactions is mostly inactive compounds and hence these reactions are considered as true detoxification reactions.
Enzymes involved are “Transferases”.
Commonly Asked Questions:
Define biotransformation of Drugs.
Define Xenobiotics.
Write a note on enzymes involved in biotransformation of drugs.
Why are drugs called Xenobiotics?