3.16 : Drug Biotransformation: Overview

Pharmaceutical substances known as xenobiotics are predominantly lipophilic and nonionized. This enables them to permeate lipid bilayers, such as cell membranes, and interact with intracellular target receptors. Lipophilic drugs have an advantage in crossing biological barriers and reaching their intended sites of action. However, lipophilic drugs often have a restricted capacity for renal expulsion or elimination from the body. When these drugs enter the kidneys and undergo glomerular filtration, they can be quickly reabsorbed from the glomerular filtrate back into the bloodstream through tubular reabsorption processes. This rapid reabsorption leads to an accumulation of the drug in the body, extending its effects and potentially triggering toxic reactions. To counteract this issue, lipophilic drugs undergo a biochemical transformation known as biotransformation or metabolism. Lipophilic drugs are chemically modified during metabolism into hydrophilic (water-soluble) derivatives. This transformation increases their solubility in water and facilitates their efficient elimination from the body via urine. While various bodily tissues can metabolize drugs, the liver is primarily responsible for this biotransformation. Within the liver, specialized enzymes catalyze the biotransformation process. Drug biotransformation involves two main enzymatically catalyzed reactions that occur sequentially. Phase I reactions are catabolic reactions that involve the functionalization of the drug molecule. These reactions introduce or expose functional groups, such as hydroxyl (-OH), amino (-NH₂), or carboxyl (-COOH) groups, to the drug molecule. This functionalization often results in the formation of metabolites that are more polar than the parent drug. Phase II reactions are anabolic and involve the conjugation of a drug or its phase I metabolite. Conjugation reactions usually involve the addition of a larger, water-soluble molecule to the drug or metabolite, such as glucuronic acid, a sulfate, or glutathione. This conjugation further increases the drug's water solubility and prepares it for elimination from the body. Generally, this metabolic process terminates the biological activity of the drug. However, in the case of prodrugs, this process enhances their activity, leading to improved therapeutic outcomes.