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METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS

METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS. Chapter 2. Roselyn Aperocho-Naranjo USPF-College of Pharmacy rose_may26@yahoo.com www.roselynnaranjo.vze.com. METABOLISM. > chemical reaction that occur in the body to maintain life

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METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS

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  1. METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS Chapter 2 Roselyn Aperocho-Naranjo USPF-College of Pharmacy rose_may26@yahoo.com www.roselynnaranjo.vze.com

  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 matter *Anabolism uses energy to build up or construct components of cells such as proteins and nucleic acids.

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

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

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

  9. General Summary of Phase I and Phase II Metabolic Pathways 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 O OH Arene Arene oxide Arenol

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

  12. Example of Oxidation Reaction Allylic Hydroxylation of Marijuana (Δ1 tetra Hydrocannabinol) CH3 CH2OH CH3 CH3 CH3 CH3

  13. Example of Oxidation Reaction Allylic Hydroxylation of Marijuana (Δ1 tetra Hydrocannabinol) (CH3) H H-C-OH H H H-C-H I (CH2OH)

  14. CH2OH CH3 CH3 7- Hydroxy Δ1 tetra Hydrocannabinol Example of Oxidation Reaction 1. Allylic Hydroxylation of Marijuana (Δ1 tetra Hydrocannabinol) CH3 CH3 CH3

  15. Example of Oxidation Reaction 2. Oxidation of THC to Carboxylic Acid derivative CH2OH COOH CH3 CH3 CH3 CH3 7- Δ1 tetra Hydrocannabinoic Acid 7- Hydroxy Δ1 tetra Hydrocannabinol

  16. Example of Oxidation Reaction 3. Oxidation of THC to Carboxylic Acid derivative and Conjugation with Glucuronic Acid R – alkyl group COOR O ll C-O- CH3 CH3 Glucuronide conjugate

  17. CH2OH CH3 CHO COOH CH3 7- Hydroxy Δ1 tetra Hydrocannabinol CH3 CH3 CH3 CH3 Oxidation Reaction • Oxidation of Benzyclic Carbon Atoms - the primary alcohol are often oxidized to form aldehydes and carboxyllic acids CH2OH –------ CHO ------------- COOH

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

  19. Oxidation Reaction • 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) • Oral hypoglycemic (Diabenese) • Sulfonylurea • Anti-inflammatory agent (Motrin) • Meprobamate • Glutethimide • Ethosuximide • Phenylbutazone

  20. Important Therapeutic Agents that undergo Aromatic Hydroxylation • Propranolol Phenobarbital back

  21. Important Therapeutic Agents that undergo Aromatic Hydroxylation • Phenytoin Phenylbutazone

  22. Important Therapeutic Agents that undergo Aromatic Hydroxylation • Ethinylestradiol Warfarin

  23. Important Therapeutic Agents that undergo Aromatic Hydroxylation • Amphetamine

  24. Important Therapeutic Agents that undergo Aromatic Hydroxylation • Deactivating groups generally slow or resist aromatic hydroxylation includes: • Chloro (Cl) • Amino group(NR3) • COOH • SO2 • 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 + O2 + H+ R-OH + NADPH + H2 O Reducing agent Molecular O2 substrate • 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

  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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