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METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS Roselyn Aperocho-Naranjo USPF-College of Pharmacy

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Presentation on theme: "METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS Roselyn Aperocho-Naranjo USPF-College of Pharmacy"— Presentation transcript:

1 METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS Roselyn Aperocho-Naranjo USPF-College of Pharmacy Chapter 2

2 METABOLISM > chemical reaction that occur in the body to maintain life > allow organisms to grow and reproduce, maintain their structures, and respond to their environments > divided into two categories: * Catabolism breaks down organic matterCatabolism *Anabolism uses energy to build up or constructAnabolism components of cells such as proteins andproteins nucleic acids.nucleic acids

3 Background Most drugs that enter the body are lipid-soluble Metabolized in the liver Drug molecules easily diffuse through membranes Reach the target site & produce a pharmacologic response

4 Background Metabolism plays a central role in the Elimination Of Drugs or Xenobiotics

5 Sites of Drug Biotransformation 2. Liver (hepatic metabolism or First Pass Effect The most important organ in drug metabolism 1. Gastrointestinal Tract Absorb orally administered drugs Some drugs may decrease Oral bioavailability Lidocaine (ineffective) Isoproterenol Meperidine Morphine Nitroglycerin Pentazocaine Propoxyphene Propranolol salicylamide 3. Blood Circulation Absorb orally administered drugs

6 General Pathways of Drug Metabolism > Phase I or Functionalization Reactions includes: * Oxidative Reaction * Reductive Reaction * Hydrolytic Biotransformation

7 General Pathways of Drug Metabolism Phase II or Conjugation Reaction * Glucoronic Acid Conjugation * Sulfate Conjugation * Conjugation with Glycine, Glutamine and other Amino Acids * Glutathione or Mercapturic Acid Conjugation * Acetylation * Methylation

8 General Summary of Phase I and Phase II Metabolic Pathways PHASE I or FUNCTIONALIZATION REACTIONS B. Reductive Reactions -Oxidation of Aromatic Moieties - Reduction of aldehydes and ketones -Oxidation of Olefins - Reduction of Nitro and Azo compounds -Oxidation of Benzyclic, Allylic carbon atoms, carbon - Miscellaneous Reductive reactions atoms Carbon atoms to carbonyl and imines -Oxidation of Aliphatic and Alicyclic carbon atoms C. Hydrolytic Reactions -Oxidation of Carbon-heteroatom systems: - Hydrolysis of Esters and Amides * Caron-Nitrogen system - Hydration of Epoxides and arene oxide by * Carbon – Sulfur system epoxide hydrase * Caron – Oxygen system -Carbon – Alcohols and Aldehydes -Other miscellaneous oxidative reactions PHASE II or CONJUGSTION REACTIONS A. Glucuronic Acid Conjugation B. Sulfate Conjugation C. Conjugation with Glycine, Glutamine and other Amino Acids D. Glutathione or Mercapturic Acid Conjugation E. Acetylation D. Methylation A. Oxidation Reactions

9 General Summary of Phase I and Phase II Metabolic Pathways PHASE I or FUNCTIONALIZATION REACTIONS B. Reductive Reactions -Oxidation of Aromatic Moieties - Reduction of aldehydes and ketones -Oxidation of Olefins - Reduction of Nitro and Azo compounds -Oxidation of Benzyclic, Allylic carbon atoms, carbon - Miscellaneous Reductive reactions atoms Carbon atoms to carbonyl and imines -Oxidation of Aliphatic and Alicyclic carbon atoms C. Hydrolytic Reactions -Oxidation of Carbon-heteroatom systems: - Hydrolysis of Esters and Amides * Caron-Nitrogen system - Hydration of Epoxides and arene oxide by * Carbon – Sulfur system epoxide hydrase * Caron – Oxygen system -Carbon – Alcohols and Aldehydes -Other miscellaneous oxidative reactions PHASE II or CONJUGSTION REACTIONS A. Glucuronic Acid Conjugation B. Sulfate Conjugation C. Conjugation with Glycine, Glutamine and other Amino Acids D. Glutathione or Mercapturic Acid Conjugation E. Acetylation D. Methylation A. Oxidation Reactions

10 OXIDATIVE REACTIONS Oxidation of Aromatic moieties -refers to the mixed-function oxidation of aromatic compounds (arenes) to their corresponding phenolic metabolites (arenols). R I R I R I OOH AreneArene oxide Arenol

11 Arene Oxides R I O Arene oxide R I O H H A. Spontaneous arrangement R I OH Arenols

12 Example of Oxidation Reaction Allylic Hydroxylation of Marijuana (Δ 1 tetra Hydrocannabinol) CH 3 CH 2 OH CH 3

13 H H-C-H I H H-C-OH H Example of Oxidation Reaction Allylic Hydroxylation of Marijuana (Δ 1 tetra Hydrocannabinol) (CH 3 ) (CH 2 OH)

14 Example of Oxidation Reaction 1. Allylic Hydroxylation of Marijuana (Δ 1 tetra Hydrocannabinol) CH 3 CH 2 OH CH 3 7- Hydroxy Δ 1 tetra Hydrocannabinol

15 CH 2 OH CH 3 7- Hydroxy Δ 1 tetra Hydrocannabinol Example of Oxidation Reaction COOH CH 3 2. Oxidation of THC to Carboxylic Acid derivative 7- Δ 1 tetra Hydrocannabinoic Acid

16 3. Oxidation of THC to Carboxylic Acid derivative and Conjugation with Glucuronic Acid COOR CH 3 Glucuronide conjugate R – alkyl group O ll C-O- Example of Oxidation Reaction

17 Oxidation of Benzyclic Carbon Atoms - the primary alcohol are often oxidized to form aldehydes and carboxyllic acids CH2OH – CHO COOH Oxidation Reaction CH 2 OH CH 3 7- Hydroxy Δ 1 tetra Hydrocannabinol CH 3 CHO CH 3 COOH

18 Oxidation of C atoms to Carbonyls & Imines - is a mixed function oxidase system which involve C atoms adjacent to carbonyl and imino (C=N) group. Oxidation Reaction OH H H H N-demethylation diazepam 3-hydroxydiazepam oxazepam

19 Oxidation at aliphatic and alicyclic C atoms - aliphatic hydroxylation commonly take place in drug molecules with straight or branched alkyl chains. Drugs that undergo Aliphatic Oxidation are the following: Valproic Acid (Depakene) – antiepileptic agent Barbiturates (Phenobarbital and Secorbarbital)Phenobarbital Oral hypoglycemic (Diabenese) Sulfonylurea Anti-inflammatory agent (Motrin) Meprobamate Glutethimide Ethosuximide Phenylbutazone Oxidation Reaction

20 Important Therapeutic Agents that undergo Aromatic Hydroxylation Propranolol Phenobarbital back

21 Important Therapeutic Agents that undergo Aromatic Hydroxylation Phenytoin Phenylbutazone

22 Ethinylestradiol Warfarin Important Therapeutic Agents that undergo Aromatic Hydroxylation

23 Amphetamine

24 Important Therapeutic Agents that undergo Aromatic Hydroxylation Deactivating groups generally slow or resist aromatic hydroxylation includes: Chloro (Cl) Amino group(NR 3 ) COOH SO 2 NH-R

25 Role of Cytochrome P-450 Monooxygenases in Oxidative Biotransformation General Equation describing the oxidation of many xenobiotics (R-H) forming a metabolite (R-OH) R-H + NADPH + O 2 + H + R-OH + NADPH + H 2 O Mixed Function in the biotransformation with Monooxygenases Requires both molecular and a reducing agent Enzyme responsible for transferring an Oxygen atom to the substrate is called Cytochrome P-450 substrate Reducing agent Molecular O2

26 What is Cytochrome P-450 structure Important features: -Plays a vital role in oxidation of lipophilic xenobiotics -metabolize almost unlimited number of diverse substrates by a variety of oxidative transformations. -located in the endoplasmic reticulum

27 …to be continued next meeting. Please prepare ½ crosswise for a short quiz… Good Luck!

28 General Pathways of Drug Metabolism Phase II or Conjugation Reaction * Glucoronic Acid Conjugation * Sulfate Conjugation * Conjugation with Glycine, Glutamine and other Amino Acids * Glutathione or Mercapturic Acid Conjugation * Acetylation * Methylation

29 Factors Affecting Dug Metabolism Age Difference Species and Strain Differences Hereditary or Genetic Factors Sex Differences Enzyme Induction Enzyme Inhibition Metabolism Pharmacologically active Metabolites

30 A. Age Undeveloped or deficient oxidative and conjugative enzyme causes a reduced metabolic capability of newborns. Metabolic reacion increases after after birth or when approaches adult levels Influence of age on drug metabolism is seen on the duration of action of the drug (sleep time) in nweborn and adults. Example: newborn mice sleeps 6 hours adult sleeps fewer than 6 minutes if given the same dose of 10mg/kg of body weight In Humans – half life of tolbutamide is 8 hours while in infants it is 40 hours.

31 B. Species 7 Strain Differences


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