Prodrugs are (bio)pharmaceutical compounds which are introduced into the body in their ‘inactive’ state before being catalyzed - normally via enzymatic action - into their ‘active’ state, to carry out their therapeutic effect.
Prodrugs rely on various metabolic or enzymatic processes within the body to convert them into their active therapeutic forms, often involving hydrolysis, oxidation, or reduction reactions catalyzed by enzymes such as esterases, proteases and phosphatases.
There are several reasons why scientists may choose to develop a prodrug rather than administering the active therapeutic drug directly. Most commonly, this approach addresses specific limitations of the active drug, such as poor solubility, limited bioavailability, undesirable side effects, or challenges in crossing physiological barriers like the blood-brain barrier (BBB).
A well-known example of a prodrug is L-Dopa, used to treat Parkinson's disease. Individuals with Parkinson's disease have low levels of dopamine neurotransmitter which is attributed to being the cause of the tremors associated with the disease. One treatment strategy is to then increased dopamine levels to reduce these tremors. However, delivering dopamine directly to the brain is challenging due to the blood-brain barrier (BBB)—a highly selective, semi-permeable membrane between the bloodstream and the brain's interstitial fluid. Because of this selectivity, dopamine cannot cross the BBB, however, transporter proteins at the BBB can recognize and transport L-Dopa, a precursor of dopamine. Once inside the brain, L-Dopa is converted by specific enzymes into dopamine, increasing neurotransmitter concentrations and helping to alleviate Parkinson's symptoms.
Prodrugs like L-Dopa highlight the strategic design behind drug development, enabling effective treatment by overcoming biological barriers and enhancing therapeutic efficacy.
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