5.1: Drug Biotransformation: Overview

Biotransformation, also known as drug metabolism, is a vital physiological process that chemically alters drugs, facilitating their elimination from the body and terminating their action. This process involves two main phases: phase I and phase II reactions. Phase I reactions, including oxidation, reduction, and hydrolysis, introduce or unmask polar functional groups on the drug molecule, thereby increasing its water solubility. By enhancing water solubility, the drug becomes more hydrophilic and is less likely to be reabsorbed in the lipophilic environment of renal tubules during excretion. This modification ensures that the drug and its metabolites are excreted efficiently via urine or bile, as hydrophilic substances are more readily eliminated by the kidneys. Phase II or conjugation reactions further enhance water solubility by attaching small polar molecules to the drug or its phase I metabolites. Examples include glucuronidation, sulfation, acetylation, methylation, and glutathione conjugation.

The liver, laden with drug-metabolizing enzymes, is the primary site for drug metabolism. However, other organs like the lungs, kidneys, intestines, and placenta also contribute. The enzymes responsible for drug metabolism fall into two categories: microsomal and non-microsomal. Microsomal enzymes in the endoplasmic reticulum catalyze most drug biotransformation reactions, while non-microsomal enzymes in the cytoplasm and mitochondria play a subsidiary role.

Drug metabolism detoxifies xenobiotics, activates prodrugs, and inactivates active drugs, preventing drug accumulation and reducing toxicity risk. However, it can also form reactive metabolites, potentially causing adverse effects. In essence, understanding biotransformation is crucial for predicting drug interactions, optimizing drug therapy, and ensuring patient safety.

Drug biotransformation or metabolism entails chemical alteration of xenobiotics, either activating or deactivating their pharmacological properties.

Metabolism converts lipophilic drugs into polar, water-soluble products, aiding excretion. For instance, the conversion of codeine to morphine.

The liver is the primary site for drug metabolism, but the lungs, kidneys, intestines, placenta, and skin also contribute.

Most drugs are metabolized in two sequential phases. Phase I reactions introduce or unmask polar functional groups through oxidative, reductive, and hydrolytic reactions, preparing the drug for phase II reactions.

In phase II, products from phase I reactions conjugate with small polar molecules like glucuronic acid, sulfate, glycine, and glutathione, forming highly water-soluble metabolites.

Microsomal enzymes found in the liver's endoplasmic reticulum, along with non-microsomal enzymes in the cytoplasm and mitochondria, catalyze most drug biotransformation reactions.

Drug's physicochemical properties, biological variations, and chemical factors influence drug metabolism, where drugs form reactive metabolites, leading to toxicity.