BIOTRANSFORMATION AND ITS ROLE IN NEW DRUG DEVELOPMENT.pptx

BIOTRANSFORMATION AND ITS ROLE IN NEW DRUG DEVELOPMENT

1. BIOTRANSFORMATION AND ITS ROLE IN NEW DRUG DEVELOPMENT SUBMITTED TO : Dr. MOHD AKBAR DAR SUBMITTED BY : SYED BASIT M.Pharm First Year ( Pharm. Chemistry )

2. CONTENTS INTRODUCTION GENERAL TERMINOLOGY CONSEQUENCES OF BIOTRANSFORMATION ENZYMES PHASES OF METABOLISM FACTORS AFFECTING BIOTRANSFORMATION ROLE OF BIOTRANSFORMATION IN NEW DRUG DEVELOPMENT 8. CONCLUSION

3. INTRODUCTION DRUG METABOLISM Drug metabolism of an enzymatic conversion from one chemical form of a substance to another. It is an essential pharmacokinetic process which converts lipid soluble and non-polar compounds to water soluble and polar compounds so that they are excreted by various processes. Liver is the major site of drug metabolism ,but specific drugs may undergo biotransformation in other tissues.

4. General Terminology Metabolism Process of converting a drug into product or inert substances after or before reaching at the site of action. Biotransformation It is a specific term used for the chemical transformation of xenobiotics in the living organisms. Xenobiotics These are all chemical substances that are not nutrient for the body (foreign body) and which enter the body through ingestion, inhalation or dermal exposure

5. CONSEQUENCES OF BIOTRANSFORMATION Biotransformation can result in activation ,inactivation or no change in pharmacological activity as listed under: ACTIVE TO INACTIVE; E.g phenobarbitone hydroxyphenobarbitone 2. ACTIVE TO ACTIVE; E.g morphine codeine 3. INACTIVE TO ACTIVE E.g levodopa dopamine

6. ENZYMES MICROSOMAL ENZYMES NON MICROSOMAL ENZYMES Smooth endoplasmic reticulum of cells of liver, git, kidney, lungs &skin. Cytoplasm, mitochondria of hepatic & other tissues(plasma). 2. Non-specific, inducible. 2. Non-inducible. 3. PHASE-I: most oxidation & reduction, some hydrolysis. 3.PHASE-I: most hydrolysis, some oxidation & reduction.

7. Reactions involved in Drug Metabolism Phase I (Non Synthetic Phase) Phase II (Synthetic Phase) Dealkylation (CH 3 CH 2 (n)CH 3 ) Glucuronidation (C 6 H 10 O 7 ) Aliphatic hydroxylation (OH) Sulfation (SO 4 ) Aromatic hydroxylation (OH) Acetylation (CH 3 CHO) Oxidation Methylation (CH 3 ) De amination (NH 2 ) Condensation (lose H 2 O) Hydrolysis Isomerisation (e. g D & L forms)

8. PHASES OF METABOLISM > PHASE I REACTIONS ; 1.OXIDATION A large number of drug substances undergoes metabolism by oxidation. These includes alcohol, aldehydes, olefins, amines, aromatic compound etc. Oxidation of Alcohol : Aliphatic and aromatic alcohols undergo oxidation to form the corresponding acids. It is catalysed by alcohol dehydrogenase. C 2 H 5 -OH (O) CH 3 -COOH Ethyl alcohol Acetic acid

9. Oxidation of Aldehyde: Aldehydes undergo oxidation to form the corresponding acids.

10. 2.Reduction A large drug substances containing aldehyde, nitro and azo groups undergo metabolism by reduction. Reduction of aldehyde Aldehydes & ketones undergoes reduction by enzymes called aldo -keto reductase. E.g Bioreduction of chloral a sedative hypnotic drug undergoes reduction to form trichloroethanol. O Ccl 3 -C-H Cl 3 C-CH 2 OH Chloral Trichloroethanol

11. 3.Hydrolysis Drugs containing ester and amide functional group undergoes metabolism by hydrolysis. e.g Aspirin undergoes metabolism by hydrolysis of the ester functional group to form salicylic acid and acetic acid.

12. >Phase-II Reactions In Phase-II the metabolites formed in Phase-I are converted to more polar and water soluble product by attaching polar and ionisable moiety such as glucuronic acid, sulfate , glycine and glutamic acid. The resulting conjugated products are relatively water soluble and readily excretable,

13. 1. Glucuronic acid Conjugation with glucuronic acid is the most common reaction. The active form of glucuronic acid is UDP-glucuronic acid. Phenolic & alcoholic hydroxyls are the most common functional group undergoing Glucuronidation in drug metabolism. UDP- glucuronyl transferase R------OH + UDP-glucuronic acid R------O-----glucuronide +UDP Drugs like morphine, acetaminophen, chloramphenicol & propranolol undergo metabolism by glucuronidation.

14. 2. Glycine Many aromatic carboxylic acids form conjugate with glycine, benzoic acid conjugates with glycine to form hippuric acid, which is a well known metabolic reaction.

15. 3. Glutamine Glutamine conjugation occurs mainly with phenylacetic acid to form phenylacetyl glutamine.

16. Factors affecting metabolism A number of factors may influence the metabolic rate of a drug. Some of them are: 1. Chemical Factors Enzyme induction Enzyme inhibition Environmental chemicals 2. Biological Factors Age Diet Sex difference Species difference Strain difference Altered physiological factors 3. Physicochemical properties of the drug.

17. Enzyme Induction The phenomenon of increased drug metabolizing ability of enzymes by several drugs and chemicals is called as enzyme induction and the agents which bring about such an effect are called enzyme inducers. E.G Oral Contraceptive CYP3A4 Inactive, Excreted Steroids Induction Rifampin

18. Enzyme Inhibition A decrease in the drug metabolising ability of an enzyme is called as enzyme inhibition. The process of inhibition may be direct or an indirect. E.G Terfenadine Active Antihistamine Inhibition Erythromycin Ketoconazole

19. ROLE OF BIOTRANSFORMATION IN NEW DRUG DEVELOPMENT A knowledge of the metabolic pathway of a drug may be used to design analogues that have a different metabolism to that of the lead. This change of metabolism is achieved by modifying the structure of the drug. These structural modifications may either make the analogue more stable or increase its ease of metabolism relative to the lead (see Table 9.4). The structural modifications should be selected so that they do not change the nature of the pharmacological activity of the drug. However, it is not possible to accurately predict whether this will be the case and so normally the activity of the analogue may only be found by experiment .

20. . Changing the metabolism of a lead may result in an analogue which exhibits a different type of activity to that of the lead. For example, the replacement of the ester group in the local anesthetic procaine by an amide group produced procainamide, which acts as an antiarrhythmic (Figur e (a).

21. It may also be used to develop analogues that do not have undesirable side effects. For example, the local anesthetic lignocaine is also used as an antiarrhythmic. In this respect, its undesirable convulsant and emetic side effects are caused by its metabolism in the liver by dealkylation to the mono-N-ethyl derivative (Figure (b) ). The removal of the N-ethyl substituents and their replacement by an a-methyl group gives the antiarrhythmic tocainide. Tocainide cannot be metabolized by the same pathway as lignocaine and does not exhibit convulsant and emetic side effects

22. BIBLIOGRAPHY Gareth Thomas ,”Fundamentals of Medicinal chemistry”. Copyright by John Wiley & sons. University of Postmouth ,UK :WILEY ;2003. Fasinu, P., J Bouic, P., & Rosenkranz, B. (2012). Liver-based in vitro technologies for drug biotransformation studies-a review.  Current drug metabolism ,  13 (2), 215-224.

23. CONCLUSION By above discussed powerpoint presentation I clearly want to convey and reveal the complete information and available data regarding Biotransformation in chemical as well as pharmacological aspects. Besides this biotransformation was found to be a tool to develop new drug. Hope that I have succeeded in delivering the complete information about biotransformation and its consequences.

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