Designing Prodrugs

When chemical modifications do not provide sufficient bioavailability, duration of action, membrane penetration or metabolic stability, a prodrug, an inactive or weakly active precursor or derivative, may be designed that is converted to the active form in the body. After absorption, a drug is transported to the liver. There it is exposed to degradation enzymes that make it more water soluble for excretion. The amount of drug that survives this first pass through the liver is called the bioavailable fraction. Esters, which are cleaved by ubiquiously present esterases, are often used as prodrugs to mask polar acid groups. A variety of chemical modifications have been used to modulate the physicochemical properties of drug molecules. However, they require specific enzymes in the target cells or organs for metabolic activation. L-DOPA is an amino acid analog of dopamine. It is delivered to the brain via an amino acid transporter and is rapidly decarboxylated. To avoid peripheral side effects, it is advisable to combine L-DOPA with polar decarboxylase inhibitors. Targeting drugs to specific organs or cells take advantage of specific metabolic transformations that occur only in these compartments of the body. Antibody-conjugated drugs are specifically delivered to those compartments or organs that present the antibody-specific recognition sites on the surface of disease-associated cells. Once in the targeted compartment, the drug is released by special mechanisms. https://sn.pub/wippd2