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 > 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 OH H OH H H diazepam 3-hydroxydiazepam oxazepam

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

Important Therapeutic Agents that undergo Aromatic Hydroxylation Propranolol Phenobarbital back

Important Therapeutic Agents that undergo Aromatic Hydroxylation Phenytoin Phenylbutazone

Important Therapeutic Agents that undergo Aromatic Hydroxylation Ethinylestradiol Warfarin

Important Therapeutic Agents that undergo Aromatic Hydroxylation Amphetamine

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

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

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

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

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

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

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.

B. Species 7 Strain Differences