Prodrugs Part I

Question 1

Role of Metabolism in Drug Design

Answer 1

Understanding drug metabolism and the chemical aspects of metabolic transformations lead to the introduction of the concept of prodrugs, active metabolites, soft and hard drugs.

Question 2

What is a prodrug?

Answer 2

A prodrug is a medication that is administered as an inactive (or less than fully active chemical derivative)

Subsequently, it is converted to an active pharmacological agent in the body, often through normal metabolic processes.

A prodrug serves as a type of precursor to the intended drug.

Question 3

Objectives of Prodrugs Design

Answer 3

Improve: Solubility / Stability / Absorption & Distribution / Site-selective delivery

Decrease toxicity, side effects and first pass effect.

Solve chemical formulation problems.

Slow and prolong drug action.

Question 4

What are the characteristics of a prodrug?

Answer 4

1. The prodrug must be readily transported to the site of action.
2. The prodrug must be selectively cleaved to the active drug utilizing special enzymatic profile of the site. (This reduces adverse effects of teh intended drug, especially important in treatments like chemotherapy)
3. Once the prodrug is selectively generated at the site of action, the tissue must retain the active drug without further degradation.

Question 5

Classification of Prodrugs

Answer 5

1. Carrier-linked Prodrug (Bipartate & Tripartate)

2. Bioprecursors

Question 6

Carrier-linked prodrugs

Answer 6

An active drug linked to a removable carrier (usually hydrolyzable group such as ester, amide, etc…) designated as the promoiety.

The promoiety alters the physical properties of the drug to increase water or fat solubility or provide site-directed delivery.

Question 7

Characteristics of an ideal drug carrier.

Answer 7

1. Protect the drug until it reaches the site of action.
2. Localize the drug at the site of action.
3. Allow for release of drug.
4. Minimize host toxicity.
5. Biodegradable, inert, and non-immunogenic.
6. Easily prepared and inexpensive.
7. Stable in the dosage form.

Question 8

Functional groups that are amenable to prodrug design.

Answer 8

1. For enhanced oral absorption: Amides
2. For Enzymatically more stable drug (than the corresponding esters): Carbamate
3. To enhance lipophilicity & membrane permeability, of water soluble drugs: Esters
4. To enhance the membrane permeability and absorption of a parent drug: oximes.

Question 9

Types of carrier linked pro-drugs

Answer 9

1. Bipartate prodrug (one carrier + one drug)
2. Tripartate prodrug (one carrier connected to a drug through a linker)
3. Mutual drug (two synergistic drugs attached to each other)

Question 10

Carrier-linked Bipartate prodrugs

Answer 10

It is one carrier attached to one drug through a covalent bond. Through enzymatic activation, the carrier releases the active drug and leaves. (Promoiety)

Question 11

Advantages of carrier-linked bipartate prodrugs

Answer 11

1. Increased water solubility.
2. Improved absorption and distribution.
3. Site specificity i.e. enhancing permeability.
4. Stability (reducing metabolic liability using prodrugs)
5. Prolonged release.
6. Minimize toxicity. (Improving selectivity for intended target)
7. Encourage patient acceptance.
8. Elimination of formulation problems.

Question 12

Bipartate prodrugs for increased water solubility.

Answer 12

Introduction of phosphates, amino acid esters or amide moieties into the molecule. (Enhance GIT solubility/absorption)

Enzymes such as phosphatases, esterases, amidases or peptidases in plasma or other tissues can then breakdown the molecules into its active form.

EX: Benzocaine

Question 13

Bipartate carrier-linked prodrugs for improved absorption & distribution

Answer 13

If the desired drug is not absorbed and transported to the target site in sufficient concentration, it can be made more water-soluble or lipid soluble depending on the desired site of action.

Corticosteroids for the topical treatment of inflammatory, allergic and pruritic skin conditions can be made mroe suitable for topical absorption by esterification or acetonidation. Once absorbed through the skin, an esterase releases the drug.

EX: Triamcinolone Acetonide & Epinephrine (Dipivefrin)

Question 14

Bipartate carrier-linked prodrugs for site specificity i.e. enhancing permeability

Answer 14

Increasing the lipophilicity of the molecule by masking the polar functional groups and hydrogen bonds with ester or amide linkers is a common approach to address poor/passive permeability.

EX: acetylation of GABA with aliphatic or aromatic carboxylic acids.

Question 15

For stability (reducing metabolic liability) using bipartate carrier-linked prodrugs

Answer 15

Prodrugs can be used to protect against rapid metabolic breakdown and prolong the half-life of the drug by masking labile functions.

EX: Naltrexone. R= Anthranilyl or Acetylsalicyl.

Question 16

For Prolonged Release using bipartate carrier-linked prodrugs

Answer 16

Utility of prolonged release of drugs is several folds.

It reduces the number and frequency of doses required.

Eliminates night-time administration of drugs and the fact that the drug is taken less frequently, patient noncompliance is minimized.

EX: Tolmetin Sodium & Tolmetin prodrug by joining it with glycine amino acid.

Peak concentration duration: 1 hour, after prodrug: 9 hours.

Question 17

To encourage patient acceptance using bipartate carrier-linked prodrugs

Answer 17

An active drug may have an unpleasant taste or odor, produce gastric irritation, or cause pain when injected. The structure of the drug could be modified to alleviate these problems, but once administered, the prodrug would be metabolized to the active drug.

EX: Sulfisoxazole (R=H), Prodrug Sulfisoxazole Acetyl (R= COCH3)

Question 18

Elimination of Formulation problems using bipartate carrier-linked prodrugs

Answer 18

Formaldehyde is a flammable colorless gas with a pungent odor that is used as a disinfectant. Solutions of high concentrations of formaldehyde are toxic.

Hexamethylenetetramine (methenamine) can be used as a prodrug for formaldehyde. It releases HCHO in acidic conditions, urine in bladder can be made acidic.

Used as urinary tract antiseptic.

The reaction of formaldehyde with ammonia produces a stable adamantine like solid compound, methenamine (Hexamethylenetetramine)

Question 19

Tripartate carrier-linked prodrugs

Answer 19

Carrier-linker-drug ==Enzyme==> Carrier + Linker-Drug

Linker-Drug (spontaneouse separation) ===> Linker + Drug

Example: Bacampicillin (a prodrug for ampicillin)

Question 20

Mutual prodrugs

Answer 20

Two pharmacologically active agents are coupled together so that each acts as a promoiety for the other agent and vice versa.

A mutual prodrug is a bipartite or tripartate prodrug in which the carrier is a synergistic drug with the drug to which it is linked.

EX: Benorylate (Aspirin + Paracetamol), Sultamicillin ‘self-protection’ and Estramustine.