Drug Metabolism or Biotransformation

Drug Metabolism

Drug Metabolism or Biotransformation

Intended learning outcomes

At the end of this lecture, students will be able to:

• Describe the drug metabolism.

• Explain the sites involved in biotransformation.

• List out the enzymes involved in drug metabolism

Metabolism or Biotransformation

• Metabolism is an essential pharmacokinetic process, which renders lipid soluble and non-polar compounds to water soluble and polar compounds so that various techniques excrete them.

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

• This is because only water-soluble substances undergo excretion. In contrast, 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 the 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 the 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 nutrients for the body (foreign to the 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 the conversion of an active drug to inactive or less active metabolite(s) called pharmacological inactivation.

• It causes the conversion of an active to a more active metabolite(s) called bioactivation.

• It causes the conversion of an inactive to more active toxic metabolite(s) called lethal synthesis.

• It causes the conversion of an inactive drug (pro-drug) to an active metabolite(s) called pharmacological activation

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

• It causes the conversion of an active drug to an active metabolite(s) having an 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)

– Skin (epithelial cells)

– Intestines

– Plasma

– Nervous tissue (brain)

– Testes (Sertoli cells)

Liver

• The primary site for the metabolism of almost all drugs because it is relatively rich in a large variety of metabolizing enzymes.

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

• Within a given cell, most drug metabolizing 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 metabolized by non-enzymatic means called 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 pseudocholine esterase enzyme.

Subcellular locations of metabolizing enzymes

Endoplasmic Reticulum (microsomes):

The primary location for the metabolizing enzymes.

(a) Phase I: cytochrome P450, flavin-containing monooxygenase, aldehyde oxidase, 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, and esterase.

(b) Phase II: sulfotransferase, glutathione S-transferase, N-acetyl transferase, catechol 0-methyl transferase, amino acid conjugating enzymes.

Mitochondria

Phase I: monoamine oxidase, aldehyde dehydrogenase, cytochrome P450.

Phase II: N-acetyl transferase, amino acid conjugating enzymes.

Lysosomes

Phase I: peptidase.

Nucleus

Phase II: uridine diphosphate-glucuronosyl transferase (nuclear membrane of enterocytes).

Drug Metabolising Enzymes

Drug Metabolising Enzymes

• A number of enzymes in animals are capable of metabolizing drugs. These enzymes are located mainly in the liver, but may also be present in other organs like lungs, kidneys, intestine, brain, plasma, etc.

• The drug-metabolizing enzymes can be broadly divided into two groups: microsomal and non-microsomal enzymes.

Microsomal enzymes: The endoplasmic reticulum (exceptionally smooth endoplasmic reticulum) of the 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 catalyze glucuronide conjugation, most oxidative reactions, and some reductive and hydrolytic reactions.

• The monooxygenases, glucronyl 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, GI 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.

Drug Metabolism

Factors Affecting Drug Metabolism

1. Species differences: eg in phenyl butazone, procaine and barbiturates.

2. Genetic differences – variation exist.

3. Age of animal –feeble in fetus, aged, newborn.

4. Sex: under the influence of sex hormones.

5. Nutrition: starvation and malnutrition

6. Pathological conditions: Liver/Kidney dysfunction

SUMMARY

• 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.

• The major site of drug metabolism is the liver.

• Within a given cell, most drug metabolizing activity is found in the smooth endoplasmic reticulum and the cytosol.

• Drug metabolism can also occur in mitochondria, nuclear envelope, and plasma membrane.

• Enzymes occurring in organelles/sites other than endoplasmic reticulum (microsomes) are called non-microsomal enzymes.

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