Lecture 11 Flashcards

Biotransformations

1
Q

Metabolism aims to…

A
  • Chemically alter the drug groups so the drug metabolite no longer binds to the receptor
  • Add polarity to increase excretion of the metabolite
  • In kidney, lower protein binding and prevents reabsorption of metabolite that is in filtrate, leading to renal excretion
  • In liver, can give molecular “handle” for transporters to excrete into bile (not always necessary); once in bile and GI tract, this prevents GI reabsorption and leads to fecal excretion
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2
Q

Increases in Polarity

A
  • Phase I Metabolism
  • Oxidation is most important mechanism in Phase I Metabolism, Hydrolysis is 2nd most important, etc.
  • Increases polarity by inserting polar groups, replacing non-polar groups with polar groups, and removing non-polar groups
  • Phase II Metbaolism adds on large, polar moieties (glucoronic acid, sulfate, etc.)
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3
Q

Assessing Polarity

A
  • log(P) where P = partition coefficient between drug in 1-octanol (mimics cell membranes) and water (pH ~ 7)
  • P = [drug in octanol]/[drug in water]
  • If amphiphilic, log(P) = 0
  • If hydrophobic, log(P) > 0
  • If hydrophilic, log(P) < 0
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4
Q

Phase I

A
  • Insertion of polar groups
  • Conversion of groups to more polar functions
  • Phase I acts to directly alter the drug
  • Sometimes requires extra steps (ex: Epoxidation rings)

Sometimes metabolism is to terminate drug activity, not increase polarity…. Can also decrease polarity to lose a functional group needed for binding

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5
Q

P450 Catalyzed Reactions

A
  • Increase polarity - aromatic hydroxylation, aliphatic hydroxylation, sulfoxidation, N-/O- dealkylation
  • Don’t increase polarity - deamination, N-oxidation
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6
Q

Phase II

A

-Conjugates - very polar moieties to drugs
Add one of following:
-Glucoronic Acid - (adds 3 OH and 1 COOH), can add OH, carboxylate, thiol, amine
-Sulfation - (very polar sulfate added), mainly phenol
-Glutathione - (adds 2 amines, 2 COOH, and 1 NH+3), mainly electrophiles, GST increases thiolate’s ability as a nucleophile

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7
Q

Acetaminophen Metabolism (Phase I)

A
  • Sulfation - transesterification, activated sulfate in PAPS, deceases log(P) by 3.4
  • Glucorondiation - formation of glycosidic bond, activated ether
  • Conjugation of Styrene Oxide - Massive change in log(P) (up to 1.2 million fold), seen with electrophile to prevent reaction with DNA and proteins, thioether bond formed
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8
Q

Oxidation v.s. Reduction

A
  • Generally drugs are oxidized, but that means their metabolites are usually electrophiles
  • Gain of electrons = Reduction
  • Loss of electrons - Oxidation
  • Oxidized compounds react to try and regain their lost electrons, therefore they are electrophiles
  • Thiols and DNA = decent biological nucleophiles (targets for electrophiles to attack)
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9
Q

Phase II Metabolism v.s. Acetaminophen Oxidation

A
  • No change in solubility
  • Big change in reactivity
  • Reactions with thiols ISN’T controlled by GST enzymes, non-specific damage
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10
Q

Reactive Intermediates

A
  • USUALLY caused by Phase I reactions since they are oxidations that create electrophiles
  • Cause most of drug metabolite toxicity
  • Add to proteins - tissue damage and/or immunotoxicity leads to lots of idiosyncratic reactions
  • Add to DNA - mutagen, carcinogenic, teratogen (not ALL added covalently)

Sometimes Phase II reactions, usually carboxylate-glucuronides

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11
Q

Summary

A
  • Increases in polarity lead to decreases in protein binding and increases in renal excretion
  • Can estimate effects on polarity of different functional groups
  • Can also turn off binding to target and terminate drug action all together
  • Phase II metabolism has larger affects on polarity and gives transporters a “handle”
  • Need to understand these transformation to prevent reactive metabolite reactions
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