BIOTRANSFORMATION

1. BIOTRANSFORMATION

2. DEFINITION • Chemical alteration of a drug/chemical inside our body is called as biotransformation/metabolism

3. Why Biotransformation? • Most drugs are excreted by the kidneys • • For renal excretion drugs should: • – have small molecular mass • – be polar in nature • – not be fully ionized at body pH • Most drugs are complex and do not have these properties and thus have to be broken down to simpler products.

4. Why Biotransformation? Drugs are lipophilic in nature • Thus readily pass across biological barriers • Strongly bound to plasma proteins • This property also stops them from getting eliminated They have to be converted to simpler hydrophilic compounds so that they are eliminated and their action is terminated.

5. Where Do Drug Biotransformations Occur? • The liver is the principal organ of drug metabolism. Other tissues that display considerable activity include the • gastrointestinal tract, • lungs, • skin, • kidneys.

6. Who is carrying out Drug Biotransformations? • Although drug biotransformation in vivo can occur by spontaneous, non-catalyzed chemical reactions, the vast majority of transformations are catalyzed by specific cellular enzymes. • At the sub cellular level, these enzymes may be located in the endoplasmic reticulum, mitochondria,cytosol, lysosomes, or even the nuclear envelope or plasma membrane.

7. Drug metabolizing enzymes • Cytochrome P450 (CYP 450) is the major drug metabolizing enzyme system in the body. • Also known as “mixed function monooxygenases” • Liver and gut wall have the greatest concentration of P450 • Almost all tissues in the body have some P450 (Lungs, Kidney, Skin, Brain, etc)

8. CYP Isoforms • CYP1A2, 2A6, 2C9, 2D6, 2E1, and 3A4 appear to be the major forms that carry out metabolic reactions .

9. CYP Isoforms% DRUGS METABOLIZED BY CYP ENZYMES

10. Biotransformation : Consequences • Active drug  Inactivation morphine  6-hydroxy morphine • Active drug  Active metabolite digitoxin digoxin • Inactive drug(prodrug)  Active drug L-dopa dopamine Enalapril Enalaprilat Bacampicillin  ampicillin

11. Phases • Biotransformation reactions can be: – Phase I reactions – Phase II reactions

12. Phase I reactions • Catabolic in nature • – e.g. Oxidation, Reduction, Hydrolysis • End-products are chemically more reactive • Metabolites are usually more polar than the parent drug. • Introduce a reactive group – ie functional group • The functional group becomes the starting point for Phase II reaction.

13. Phase I reactions • Cytochrome P450 is the major enzyme system (Oxidations, reductions, etc.) Phase I metabolites may be: • Inactive • Equally Active • More Active • Toxic • Activated - “prodrug” • Polar metabolites may be excreted.

14. Phase I reactions

15. Phase II reactions • Synthetic processes • If a drug is not rendered to hydrophilic molecule by Phase-I reactions, Phase –II is required. • An endogenous substrate is coupled to an existing (or phase I formed) conjugation site. • Forms a highly polar conjugate • Phase II reactions usually occur after Phase I but can also take place earlier than Phase I

16. Phase II reactions

17. Drug molecule I More hydrophilic metabolite Conjugate II De-conjugation and reuptake (entero-hepatic cycling) Bile Kidney Intestines Urine Feces

18. Enzyme Induction • Reversible increase in enzyme concentration • Resulting from administration of certain drugs • May increase the metabolism of other drugs taken concurrently Consequences: • Decreased duration of action of an active drug due to fast inactivation . • Increased intensity of action of an inactive drug due to fast activation

19. Enzyme Induction

20. Enzyme Inhibition • Some drugs can block P450 enzymes that metabolise other drugs • Unlike induction, enzyme inhibition usually begins with the first dose of the inhibitor. Consequences: • May increase serum concentrations of second drug • Can lead to toxicity

21. Enzyme Inhibition