MED ORG LEC - 03 Chemical Aspects of Drug Metabolism

Metabolism

• Conversion of the active drug molecule to inactive products (metabolites), waiting excretion

• Most drug _____ is done by the liver

Elimination

Metabolism and excretion are often grouped under the word “_____”

Parent

Original molecule is called _____

Metabolites

Products after metabolism are called _____

Nonpolar

Most parents get into the bloodstream and are distributed as _____ molecules. To get out of the body, they must be converted to more polar metabolites.

Deactivation

Parent: Active

Metabolite: Inactive

Overall Effect: ?

Most common case

Activation

Parent: Inactive

Metabolite: Active

Overall Effect: ?

Case for prodrugs

Continued Activity

Parent: Active

Metabolite: Active

Overall Effect: ?

Increases DoA; “active metabolites”

Toxicity

Parent: Active

Metabolite: Toxic

Overall Effect: ?

Special cases

Altered Activity

Parent: Active

Metabolite: Active (other)

Overall Effect: ?

Special cases

Example of Deactivation

Example of Activation

Example of Continued Activity

Example of Toxicity

Functionalization

• Phase I Reaction

• Converts a drug into a more polar metabolite, either by adding a small functional group or “unmasking” them from the original molecule

• Small changes

Conjugation

• Phase II Reaction

• Attachment of a (usually polar) molecule to assure that the drug metabolite is very readily excreted

• Requires cofactors that supply the group to be attached

• Big attachments

• Converts metabolite → hydrophilic

Reactions in Phase I/Functionalization

• Oxidation

• Reduction

• Hydrolysis

Oxidation

Reduction

C-Redox Aromatic Hydroxylation

Benzylic Carbon

• Directly attached to the ring

• Susceptible to Oxidation

Vinylic Carbon

• Carbon that is apart of a double bond

• C=C

Oxidation of a-Carbons

N-Redox

• becomes primary amines

S-Redox

• Redox at the sulfur atom

• Oxidation of hydrogen

Dealkylation

• Removal of alkyl group

N-demethylation

What reaction is this?

N-deethylation

What reaction is this?

Oxidative Elimination

Hydrolysis

What reaction is this?

Amides

• Has 2 i’s

Esters

• Has 1 i

• Has faster rate

• More electrophilic

Reactions in Phase II/Conjugation

• Glucuronidation

• Glycine Conjugation

• Glutathione Conjugation

• Acetylation

• Sulfation

• Methylation

Glucuronidation

• Cofactor: UDP-glucuronic acid

• Enzyme: UDP-glucuronosylacyltransferase (UDP GAT)

• Most common Phase II Process

• Can result to:

  • O-glucuronides

  • N-glucuronides

  • S-glucuronides

• Last Phase II Process to develop in neonates

• Clinical Correlate:

  • Gray Baby Syndrome (toxicity from chloramphenicol—antibiotic)

  • Hyperbilirubinemia

Glycine Conjugation

• Cofactor: Glycine itself

• Enzyme: Glycine N-acetyltransferace

• Not that common

GSH Conjugation

• Cofactor: Glutathione (GSH)

• Enzyme: Glutathione S-transferase (GST)

• Targets:

  • halides

  • sulfates

  • sulfonates

  • phosphates

  • nitrates

• Biochem Correlate:

  • Glutathione is composed of E, C, and G

• GSH can be reactivated by adding SH groups from other molecules

Acetylation

• Cofactor: Acetyl-CoA

• Enzyme: N-acetyltransferase (NAT)

• Most common pathway for primary amines, even including amides, sulfonamides, and hydrazo groups

• “HIPS”

  • hydralazine

  • isoniazid

  • procainamide

  • sulfonamides

Sulfation

• Cofactor: 3-phosphoadenosyl-5’-phosphosulfate (PAPS)

• Enzyme: Sulfotransferases

• Especially important for phenols (ex. APA, catecholamines, thyroxine, bile acids, phenolic drugs, steroids)

Methylation

• Cofactor: S-adenosylmethionine (SAM/AdoMet); Occasionally, methylenetetrahydrofolate

• Enzyme: Methyltransferases

• Important for synthesis of neurotransmitters

Reduction

Determine the metabolic reaction

Demethylation

Determine the metabolic reaction

Aromatic Hydroxylation

Determine the metabolic reaction

Epoxydation

Determine the metabolic reaction

N-demethylation

Determine the metabolic reaction

Glycine Conjugation

Determine the metabolic reaction

Hydrolysis

Determine the metabolic reaction

Demethylation

Determine the metabolic reaction

Acetylation

Determine the metabolic reaction

Diazepam

What is this Structure?

Enzyme Inhibition

• Reduction of enzyme activity

• Increases drug in body

• Potential Problem? Toxicity

Enzyme Induction

• Improvement of enzyme activity

• Decreases drug in body

• Potential Problem? Decreased efficacy/Failure of therapy

TRUE

TRUE OR FALSE

Phase I does not always mean first. There are some drugs that go straight to Phase II