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METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS. Chapter 2. Roselyn Aperocho-Naranjo USPF-College of Pharmacy [email protected] www.roselynnaranjo.vze.com. METABOLISM. > chemical reaction that occur in the body to maintain life - PowerPoint PPT Presentation
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METABOLIC CHANGES OF DRUGS AND RELATED ORGANIC COMPOUNDS
Roselyn Aperocho-NaranjoUSPF-College of [email protected]
www.roselynnaranjo.vze.com
Chapter 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.
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
Background
Metabolism plays a central role in the
EliminationElimination
Of Drugs or XenobioticsOf Drugs or Xenobiotics
Sites of Drug Biotransformation
2. Liver (hepatic metabolism or First Pass Effect
The most important organ in drug metabolism
1. Gastrointestinal TractAbsorb orally administered drugs
Some drugs may decrease Oral bioavailability
Lidocaine (ineffective)IsoproterenolMeperidineMorphine
NitroglycerinPentazocainePropoxyphene
Propranololsalicylamide
3. Blood CirculationAbsorb 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 REACTIONSA. Glucuronic Acid ConjugationB. Sulfate ConjugationC. Conjugation with Glycine, Glutamine and other Amino AcidsD. Glutathione or Mercapturic Acid ConjugationE. AcetylationD. 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 REACTIONSA. Glucuronic Acid ConjugationB. Sulfate ConjugationC. Conjugation with Glycine, Glutamine and other Amino AcidsD. Glutathione or Mercapturic Acid ConjugationE. AcetylationD. 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 OHArene Arene oxide
Arenol
Arene Oxides
R I
I O
Arene oxide
R I
O HH
A. Spontaneous arrangement
R I
I OH
Arenols
Example of Oxidation Reaction
Allylic Hydroxylation of Marijuana (Δ1 tetra Hydrocannabinol)
CH3
CH3
CH3
CH2OH
CH3
CH3
HH-C-H I
HH-C-OH H
Example of Oxidation ReactionAllylic Hydroxylation of Marijuana (Δ1 tetra Hydrocannabinol)
(CH3)
(CH2OH)
Example of Oxidation Reaction1. Allylic Hydroxylation of Marijuana (Δ1 tetra Hydrocannabinol)
CH3
CH3
CH3
CH2OH
CH3
CH3
7- Hydroxy Δ1 tetra Hydrocannabinol
CH2OH
CH3
CH3
7- Hydroxy Δ1 tetra Hydrocannabinol
Example of Oxidation Reaction
COOH
CH3
CH3
2. Oxidation of THC to Carboxylic Acid derivative
7- Δ1 tetra Hydrocannabinoic Acid
3. Oxidation of THC to Carboxylic Acid derivative and Conjugation with Glucuronic Acid
COOR
CH3
CH3
Glucuronide conjugate
R – alkyl group O ll C-O-
Example of Oxidation Reaction
Oxidation of Benzyclic Carbon Atoms - the primary alcohol are often oxidized to form aldehydes
and carboxyllic acids
CH2OH –------ CHO ------------- COOH
Oxidation Reaction
CH2OH
CH3
CH3
7- Hydroxy Δ1 tetra Hydrocannabinol
CH3
CH3
CHO
CH3
CH3
COOH
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.
Oxidation Reaction
OH
H
OH
H
HN-demethylation
diazepam 3-hydroxydiazepam oxazepam
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
Oxidation Reaction
Important Therapeutic Agents that undergo Aromatic Hydroxylation Propranolol Phenobarbital
back
Important Therapeutic Agents that undergo Aromatic Hydroxylation Phenytoin Phenylbutazone
Ethinylestradiol Warfarin
Important Therapeutic Agents that undergo Aromatic Hydroxylation
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 manyxenobiotics (R-H) forming a metabolite (R-OH)
R-H + NADPH + O2 + H+ R-OH + NADPH + H2 O
Mixed Function in the biotransformation with MonooxygenasesRequires both molecular and a reducing agentEnzyme responsible for transferring an Oxygen atom to the substrate is called Cytochrome P-450
substrate Reducing agent
Molecular O2
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. 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