Metabolism of drugs Pharmacokinetics

Metabolism of drugs Pharmacokinetics

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3. Contents​
•Metabolism (active --> inactive)​
•Prodrug (inactive --> active)​
•Drug with equally active metabolite (active --> active)​
•First Pass Metabolism (presystemic biotransformation)​
•Chemical pathway of Metabolism​
•Enzyme induction and Enzyme inhibition​
•Factors affecting Metabolism​

4. Metabolism
•Biotransformation means enzyme catalyzed biochemical transformation
of drugs within the living organism. ​
•The metabolites thus formed are much less lipid soluble, hence
not reabsorbed from the renal tubules and thus are finally excreted. ​
•The biotransformation of drugs, which is the more preferred term, occurs
mainly in liver, although kidney, intestine, adrenal cortex, lungs, placenta
and skin may also be involved to some extent. ​
•The dead tissues, like nails and hair are not involved in
drug biotransformation.​

5. Metabolism (active --> inactive)​
•This is usual case: e.g. Phenobarbitone (active metabolite)
is converted to hydroxy Phenobarbitone (inactive metabolite)​
Prodrug (inactive --> active)​
•​It is useful when drug undergoes first pass metabolism
•E.g. L-Dopa (inactive) converts to Dopamine (active)​
Drug with equally active metabolite (active --> active)
•It is beneficial for long duration of action
•E.g. Diazepam (active) is converted to Oxazepam (active)

6. First Pass Metabolism
•All drugs taken orally, first of all, pass through GIT wall and then
through portal system, before reaching the systemic circulation.
• First-Pass Metabolism or the pre-systemic metabolism or the First-
Pass Effect means the drug metabolism occurring before the drug
enters the systemic circulation.
•The net result is the decreased bioavailability of the drug and
consequently a diminished therapeutic response, because a
significant amount of the drug is inactivated before reaching the
systemic circulation.
•The first-pass effect may be bypassed if the drug is administered
parenterally.

7. Chemical Pathways
•Phase I reactions
This are Degradative reactions, makes drug small and polar molecule
Includes oxidation, reduction and hydrolysis reactions
•Phase II reactions
This are synthetic reaction also called Conjugation
The metabolite formed are small, inactive and water soluble

8. Phase – I Reactions
•Oxidation
Microsomal
Non - microsomal
•Reduction
Microsomal
Non - microsomal
•Hydrolysis
Microsomal
Non - microsomal
Microsomal
This are enzymes located on SER, of the
Liver. This is also called Cytochrome P450
system of enzymes.
Non - Microsomal
This are enzymes from mitochondria,
cytoplasm, and plasma. Includes enzymes
like oxidase, transferase, amidase, etc.

9. Oxidation Reactions
•Aromatic/Aliphatic hydroxylation (addition of OH group)
•N/S Dealkylation or Oxidation
•Deamination or Sulfurization
•Cytoplasmic oxidation and Mitochondrial oxidation



Refer examples from H. L. Sharma

10. Reduction Reactions
•Nitro Reduction
•Azo Reduction
•Keto Reduction
Hydrolysis Reactions
•Very Rarely observed reaction

11. Phase – II: Conjugation
•Glucuronide Conjugation
•N – acetyl conjugation
•Sulfate Conjugation
•Amino acid Conjugation
•Methyl Conjugation
•Glutathione Conjugation
•Phosphate Conjugation

12. Glucuronide Conjugation
UDPGA (uridine diphosphate glucuronic acid)
Sulfate Conjugation
N - acetyl Conjugation

13. Enzyme Induction and Enzyme inhibition
•Some drugs, that have ability to induce the enzymes involved in
process of metabolism.
•While some others, have ability to inhibit the enzymes involved in
process of metabolism.
•This kind of drugs when administered can show toxicity or can reduce
the effect of other co-administered drugs.
•Hence Enzyme inducers reduce the effect of drugs by metabolizing
them at faster rate.
•And Enzyme inhibitors can result in sudden toxicity of other drug due
to inhibition of metabolism

16. Factors Affecting Metabolism
•Age
•Gender
•Species
•Race
•Genetic Variation
•Nutrition and Diet
•Disease
•Drug - Drug Interaction

17. To be Finished soon….