Lecture 11 Flashcards
Biotransformations
Metabolism aims to…
- 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
Increases in Polarity
- 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.)
Assessing Polarity
- 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
Phase I
- 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
P450 Catalyzed Reactions
- Increase polarity - aromatic hydroxylation, aliphatic hydroxylation, sulfoxidation, N-/O- dealkylation
- Don’t increase polarity - deamination, N-oxidation
Phase II
-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
Acetaminophen Metabolism (Phase I)
- 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
Oxidation v.s. Reduction
- 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)
Phase II Metabolism v.s. Acetaminophen Oxidation
- No change in solubility
- Big change in reactivity
- Reactions with thiols ISN’T controlled by GST enzymes, non-specific damage
Reactive Intermediates
- 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
Summary
- 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