Medicinal Chemistry

Drug Metabolism

Phase II Metabolic Routes

• Known as conjugation reactions• Involve the attachment of a group or a molecule to the drug or

metabolite• May occur at any point in the metabolism process• Often the final step in the metabolic pathway before excretion• Products of these reactions are known as conjugates• Normally water soluble and usually excreted in the urine and/or

bile• Conjugates are usually pharmacologically inactive• Reactions commonly involved in phase II conjugation are

acylation, sulphate formation, and conjugation with amino acids, glucuronic acid, glutathione, and mercapturic acid.

• Methylation is a minor metabolic route, but it can be a major route for phenolic hydroxy groups

• In all cases, the reaction is usually catalyzed by specific esterase

Prodrugs• Inactive compounds that yield an active compound in the body• Conversion is frequently carried out by enzyme-controlled

metabolic reactions and less frequently by chemical reactions within the body

Prodrugs are used as a way to:• Increase lipid or water solubility• Improve that taste of a drug to make it more patient compatible• Alleviate pain when the drug is administered parenterally by

injection• Reduce toxicity• Increase chemical stability• Increase biological stability• Change the length of the time of duration of action• Deliver the drug to a specific site in the body

Continue…• Prodrugs can be broadly classified into two groups:1. Bioprecursors2. Carriers• They may also be sub-classified according to the nature of their

action (e.g. photoactivated drugs)

Bioprecursor Prodrugs• Inactive compounds that are converted into the active drug form

through the action of metabolism• Conversion may involve a single step or a series of steps• Oxidation, reduction, and phosphorylation are all involved in the

conversion of some prodrugs into active drugs• Reduction reactions are not as common as oxidation• Phospohorylation occurs in the activation of a number of antiviral

drugs

Carrier Prodrugs• Are formed by combining an active drug with a carrier species to

form a compound with the desired chemical and biological characteristics

• The link between the drug and the carrier must be a group (e.g. ester or amide) that can be easily metabolized once absorption has occurred or the drug has been delivered to the required body compartment

• Carrier prodrugs that consist of a drug linked by a functional group to the carrier are known as bipartate prodrugs. Tripartate drugs are those in which the carrier is linked to the drug by a link consisting of a separate structure

Continue…• The choice of the functional group used as a metabolic link depends both

on the functional groups occurring in the drug molecule and the need for the prodrug to be metabolized in the appropriate body compartment

Using prodrugs to improve absorption and transport through membranes

Improving Patient Acceptance• Palmitic acid and other long chain fatty acids are often used as

carriers, since they usually form prodrugs with bland taste

Slow Release• Provided by the slow hydrolysis of amide and ester linked fatty acid carriers

Site Specifity

Minimizing Side Effects

THE END OF THE COURSE