Lecture 20

Question 1

Bioactivation

Answer 1

• 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

Question 2

Prodrugs

Answer 2

• 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

Question 3

Esters

Answer 3

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

Question 4

Other Prodrug Forms

Answer 4

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

Question 5

Activation steps

Answer 5

• 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

Question 6

Drug Targetting

Answer 6

-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

Question 7

PK + Prodrugs

Answer 7

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

Question 8

Toxic Metabolites

Answer 8

• 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)

Question 9

Common Reactive Intermediates

Answer 9

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

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

Question 10

Protective Mechanisms (2)

Answer 10

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)