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Renin Angiotensin Mechanism.

Elimination: Introduction to Biotransformation.

 

  • 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.

  1. 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.

  1. 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.

  1. 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.

  1. 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:

  1. Define biotransformation of Drugs.

  2. Define Xenobiotics.

  3. Write a note on enzymes involved in biotransformation of drugs.

  4. Why are drugs called Xenobiotics?
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