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Flashcards in Lecture 20 Deck (10)
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1
Q

Bioactivation

A
  • Subset of metabolism
  • “dark side” and a “light side”
  • Dark side - generation of reactive, toxic metabolites
  • Light side - Generation of bioactive drug
  • Possible to have a mixed outcome of the two
2
Q

Prodrugs

A
  • Modification of drug to improve physicochemical, biopharmaceutical, or PK parameters
  • Includes solubility, stability, metabolism, bioavailability (increased GI absorption), tissue targeting
  • May be necessary for uptake and bioactivation (passing membranes)
  • ~10% of drugs worldwide are prodrugs
3
Q

Esters

A
  • Most common prodrug (~50%)
  • Cleaved by esterases
  • Increased lipophilicity
  • Alkyl and arylesters increase bioavailability
  • Phosphate esters increase aqueous solubility
4
Q

Other Prodrug Forms

A
  • Carbonate and carbamates - increased parenteral administration
  • Amides - enhance oral absorption (specific interactions with intestine uptake transporters)
  • Oximes - increased membrane permeability and absorption
5
Q

Activation steps

A
  • Some prodrugs require multiple activation steps before the active drug is exposed
  • 5-FU is an example, it decreases GI toxicity and increases tumor selectivity
  • Must go through CES, CDA, and ThdPase enzymes before it is in its active form
6
Q

Drug Targetting

A

-Cancer chemotherapy is an example
-Targets to exploit the properties of the tumor
-Hypoxia, pH, enzymes, surface antigens, etc. can all be characteristics it targets
EX: L-DOPA in the brain, prodrug to replace dopamine lost in Parkinson’s. Normal dopamine can’t pass BBB, prodrug allows for increased distribution into the brain via the LAT1 transporter
EX: Infectious disease, prodrugs utilizing the bacteria, viral, or parasite enzymes

7
Q

PK + Prodrugs

A
  • Depending on the modification, any aspect of PK (ADMET) can be altered with prodrug
  • Can overcome limitations of the initial, parent drug
8
Q

Toxic Metabolites

A
  • Reactive intermediates that modify macromolecules (Acetaminophen and isoniazid can go through this)
  • Often from electrophiles created by P450 metabolism
  • Can cause damage to DNA (carcinogens)
  • The damage to the DNA CAN be therapeutic (chemotherapies)
9
Q

Common Reactive Intermediates

A
  • Epoxides
  • Quinones
  • Free Radicals (lipid peroxidation)
  • ROS (super oxide, hydrogen peroxide, hydroxyl radical)

All can attack and modify macromolecules (DNA, RNA, proteins)

10
Q

Protective Mechanisms (2)

A
  1. Phase II Metabolism (mainly GSH) - GSH can spontaneously react and conjugate enzymatically to react with reactive intermediates (or Phase I metabolites)
  2. Cellular Antioxidants

If these are depleted, toxicity can occur (acetaminophen)