Prodrugs and Drug Latentiation

Question 1

Prodrugs

Answer 1

Compounds that are initially inactive but later activated by either chemical or metabolic processes

Question 2

Hard drug

Answer 2

Drug that has been designed to be resistant to metabolic events

Question 3

Soft drug

Answer 3

Drug that has been designed to become metabolically inactivated after serving its purpose

Question 4

2 routes by which prodrugs are activated in a physiological setting

Answer 4

1. Metabolic enzymes

2. Chemical transformations (hydrolysis, decarboxylation)

Question 5

Carrier-linked prodrugs

Answer 5

Attached through a metabolically-labile linkage to another molecule (the promoiety)

Question 6

Mutual prodrugs

Answer 6

Both the prodrug and the promoiety have activity

Question 7

Bioprecursors

Answer 7

Prodrugs that rely on metabolism to introduce the functionality necessary for an active compound

Question 8

Most common type of prodrug for carboxylic acids and alcohols

Answer 8

Esters

Question 9

Esters that can be hard to hyrdrolyze by esterases and how this can be circumvented

Answer 9

Sterically-hindered esters can be hard to hydrolyze

Can sometimes be circumvented by using a double-ester

Question 10

Why amides aren’t good prodrugs for amines

Answer 10

Amides are fairly stable to chemical hydrolysis

Amidases aren’t as common or promiscuous as esterases

Question 11

Prodrugs of amines

Answer 11

Azo compounds (can be reduced to amines)

Question 12

Prodrugs of carbonyl compounds

Answer 12

Aldehydes and ketones can be converted to acetal-like linkages with oxygen, nitrogen, and sulfur heteroatoms

Question 13

Which is more common, oxidative or reductive activation of prodrugs?

Answer 13

Oxidative activation- high prevalence of cytochrome P 450s

Question 14

Prodrug activation via phosphorylation

Answer 14

Commonly used by antiviral agents: disrupt synthesis and function of DNA/RNA

Question 15

Activation via chemical processes

Answer 15

Can achieve selective activation based on the chemical environment of tissues (ex- drugs activated in acidic environment of stomach)
Tough to control: chemical reactions occur automatically

Question 16

Advantages of prodrugs

Answer 16

Site-selective delivery of drug

Increase drug efficacy and reduce non-specific toxicity

Question 17

Most common tissue-selective carrier promoiety that prodrugs can be coupled with

Answer 17

Antibodies

Question 18

Tumor-activated prodrugs

Answer 18

Cancerous cells often exhibit increased activity for a number of metabolic enzymes, allowing certain anti-cancer agents to become selectively activated in tumor cells

Question 19

Crossing the blood-brain barrier

Answer 19

CNS prodrugs need to be lipophilic: blood-brain barrier is lipophilic

Question 20

Selective delivery to the GI tract

Answer 20

Colon has a variety of glucosidase enzymes found nowhere else in the human body
Glucoside-drug conjugates can be selectively unmasked in the colon