ADMET: Absorption Prodrugs

Objective

Why do we care about prodrugs?

there are a large number of approved therapeutic agents that are administered in the form of a prodrug

Objective

What is a prodrug?

a pharmacologically inactive compound that is converted into an active drug by metabolic transformation

Objective

What are reasons for prodrug strategies? (7)

- Aqueous solubility

- Absorption & distribution

- Metabolic instability

- Prolonged release

- Toxicity

- Patient acceptability

- Formulation issues

Functionalizing __________________ to increase water solubility

lipophilic drugs

Objective

Example of increasing aqueous solubility: Methyprednisolone --> methylprednisolone sodium succinate

methylprednisolone is the active form. It is not soluble in water

- methylprednisolone sodium succinate is the prodrug, soluble in water

Objective

Example of increasing aqueous solubility:

Etoposide --> etoposide phosphate

etoposide is the active form, converted to etoposide phosphate, prodrug

Example of increasing aqueous solubility:

SN-38 --> irinotecan

irinotecan prodrug, increases aqueous solubility

Example of increasing aqueous solubility:
Phenytoin --> fosphenytoin

Objective

Example of functionalizing to improve absorption:

Acyclovir --> Valacyclovir

- Oral BA of acyclovir: 15-30%, requires 5x per day dosing

- oral BA of prodrug, valacyclovir is 55%, allows for less frequent dosing (3x a day)

Objective

Example of functionalizing to improve absorption:

epinephrine --> dipivefrin

- epinephrine: typical dosage is 1 drop of 1.0% twice daily

- dipivefrin: lipophilic prodrug of epinephrine, better absorption, typical dosage: 1 drop of 0.1% twice daily

Example of functionalizing to improve absorption:
ampicillin --> bacampicillin --> cefpodoxime and cefuroxime

Objective

Example of functionalizing to improve absorption:

enalaprilat --> enalapril

- enalaprilat not orally BA

- enalapril has good oral BA (60%)

Objective

Functionalizing to improve distribution into the CNS:

gamma-amino butyric acid (GABA) --> progabide

- progabide is the lipohilic prodrug of GABA, reported to have much better CNS penetration than GABA itself

Functionalizing to use active transport systems to get a drug into the CNS:

L-dopa/levodopa --> dopamine

- levodopa is the prodrug of dopamine

- dopamine is not able to peneratrate the CNS

Example of avoiding/reducing the first-pass effect: Naltrexone

Naltrexone is well-absorbed orally, but undergoes extensive first-pass metabolism

- Ester prodrugs avoid some first-pass metabolism and increase oral bioavailability by 28- to 45- fold

Example of avoiding/reducing the first-pass effect: Propranolol

- propranolol is well- absorbed orally

- undergoes extensive first-pass metabolism

- hemisuccinate ester prodrug avoids some first-pass metabolism and increases BA by 8-fold

Objective

Example of avoiding/reducing the first-pass effect: acyclovir

acyclovir (Zovirax®)

prodrug

Objective

Prodrug strategy: What are benefits of prolonged release? (6)

- reducing frequency of doses required

- eliminating need for nighttime administration

- minimizing patient noncompliance

- eliminating peaks/valleys of drug concentrations in body

- reducing the potential for toxicity

- reducing GI side-effects

Objective

Example of prolonged-release: antipsychotic: Haloperidol --> Haldol D

Haldol D prodrug dosed less often

Objective

Example of prolonged release: antipsychotic: Fluphenazine deconoate and fluphenazine enanthate

fluphenazine deconoate and fluphenazine enanthate dosed less

Prodrug toxicity

avoiding irritation/GI toxicity due to acidic functional groups

Objective

Prodrug: Toxicity: dipivefrin

dipivefrin prodrug

Objective

Prodrug: toxicity: nabumetone

nabumetone inactive prodrug avoids causing

direct GI toxicity/irritation

due to acidic functional group

Objective

Prodrug: toxicity: 5-FU -> capecitabine

capecitabine prodrug has greater TI than 5-FU

Prodrugs: Patient acceptibility

- eliminating pain on injection
- masking bitter taste

Objective

Prodrug: Patient acceptibility: clindamycin phosphate (eliminating pain)

clindamycin phosphate prodrug eliminating pain on injection

Objective

Prodrug: Patient acceptability: clindamycin palmitate HCl (masking bitter taste)

clindamycin palmitate HCl masks bitter taste

Objective

Prodrug: Patient acceptability: acetyl sulfisoxazole (masking bitter taste)

acetyl sulfisoxazole masks bitter taste

Objective

Prodrug formulation issues: Volatility and toxicity: Methenamine

Methenamine prodrug breaks down to formaldehyde under right conditions