The Journey of a Drug: From Ingestion to Elimination
Introduction
Xenobiotics are compounds that can be accidentally ingested, taken as drugs, or produced in the body through external metabolism. The pharmacological effect of a drug happens when it directly interacts with a receptor or alters the physiological process that regulates functions. This is known as the mechanism of action. The specific location where a drug initiates events leading to a biological effect is called the site of action.
Mechanism Of Action
A drug’s mechanism of action is the biochemical or physical process occurring at the site of action to produce a pharmacological effect. This action is usually mediated through receptors, with cellular enzymes, structural, and transport proteins being prime examples of drug receptors.
Liberation And Absorption
Intravenous (IV) delivery is the most direct drug administration route, delivering the complete dose into the bloodstream. However, for practicality and patient preference, other methods are used, including:
- Oral (most common)
- Intramuscular
- Transdermal
- Sublingual
Oral administration differs from IV because the drug must pass from the gastrointestinal (GIT) tract into the vascular system through absorption. To be absorbed, a compound must separate from its formulation into digestive fluid, a process called liberation.
During absorption, the drug crosses GIT and vascular membranes, mainly through passive diffusion and less commonly via active transport. The absorption rate is crucial for oral administration. Generally, absorption is much faster than elimination. Bioavailability refers to the amount of drug absorbed compared to the administered quantity.
Distribution
Once in the bloodstream, the drug undergoes distribution, spreading from its entry point (e.g., digestive tract, infusion catheter) through the circulatory system and into various tissues. Some drugs remain in the plasma (e.g., Ibuprofen), while others localize in tissues (e.g., chloroquine).
Drug distribution to a specific body site depends on factors like:
- Drug size: Larger size generally means less distribution.
- Degree of ionization: Drugs are distributed in their ionized form.
- Lipid solubility: Higher lipid solubility usually leads to greater distribution.
- Extent of protein binding: Protein-bound drugs act as a reservoir, while the unbound (free) fraction is responsible for biological effects. Acidic drugs often bind to albumin, while basic drugs prefer globulin and lipoproteins.
- Body composition
- Tissue perfusion
Metabolism
Metabolism is how the body chemically alters exogenous or endogenous compounds. In drug therapy, metabolism usually enhances xenobiotic excretion, primarily by increasing water solubility. However, this doesn’t always mean deactivation or detoxification. For instance:
- Acetaminophen hepatotoxicity is caused by a minor metabolite, not the parent compound.
- Tamoxifen, a breast cancer drug, and its metabolites have equal or greater anti-cancer activity compared to the parent drug.
Some drugs, like Tamoxifen, codeine, and acetyl-salicylate, are delivered as inactive or low-activity prodrugs, requiring further metabolism for full effect.
Human drug metabolism primarily results from enzymatic activity, often described using Michaelis-Menten kinetics as first-order or zero-order processes. Most drugs exhibit first-order metabolism, where the rate is proportional to drug concentration. However, some drugs follow zero-order kinetics, where enzyme availability becomes the limiting factor, making the metabolism rate independent of drug concentration.
Types Of Metabolism
Metabolic processes are broadly categorized into two main categories (sometimes three):
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Phase 1 metabolism: Involves chemical modifications like oxidation, reduction, hydrolysis, or removing a non-polar group (e.g., demethylation). This phase can decrease or sometimes increase toxicity.
- Oxidation reactions: Examples include alcohol detoxification, where alcohol dehydrogenase and aldehyde dehydrogenase oxidize alcohol to aldehyde and then to acid, respectively.
- Reduction reactions: Some reductases containing cytochrome P450 and flavoproteins reduce nitrogen compounds to amines and aldehydes/ketones to alcohols.
- Hydrolysis: This reaction splits the toxicant into smaller fragments by adding water. Esters, amines, hydrazines, and glycosidic bonds are commonly biotransformed through hydrolysis.
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Phase 2 metabolism: Involves conjugating xenobiotics to a water-soluble moiety like glucuronic acid, sulphate, or glutathione.
- Conjugation reactions: This involves adding molecules normally present in the body to the active site.
- Glucuronic acid conjugation: The most common phase 2 reaction (e.g., bilirubin excretion as glucuronide).
- Sulphate conjugation: Decreases xenobiotic toxicity, making them readily excreted in urine.
- Glutathione conjugation
- Conjugation reactions: This involves adding molecules normally present in the body to the active site.
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Phase 3 metabolism (sometimes included): Refers to the activity of transporters like glycoproteins, which regulate drug activity and metabolism without altering chemical structures.
Excretion/Elimination
Excretion is the final removal of drugs from the body. While it can occur through sweat, breath, breast milk, and even across the placenta, the most common routes are urine and stool, depending on the compound’s water solubility. The rate of urinary elimination can be estimated using the glomerular filtration rate.
