Bioavailability refers to the rate and total amount of an active substance, such as a medication or nutrient, that is absorbed from its dosage form and successfully reaches the systemic circulation. This fraction of the administered dose then becomes available to exert its effect at the target site within the body. If a substance has low bioavailability, a large portion of the dose is lost to processes like incomplete absorption or metabolic breakdown, requiring a higher dose to achieve the desired concentration.
Intrinsic Properties Determining Bioavailability
The inherent characteristics of a substance dictate its potential for absorption and act as the primary constraints on its bioavailability. The ability of a compound to dissolve, known as solubility, is paramount; a drug must first dissolve in the gastrointestinal fluids before it can be absorbed across the intestinal wall. If a substance is poorly soluble, a significant portion may pass through the digestive tract and be eliminated before entering the circulation.
Permeability is the second factor, referring to the compound’s ability to physically cross the lipid-based cell membranes lining the gut. Substances must possess a certain degree of fat-solubility, or lipophilicity, to diffuse passively through this membrane barrier and enter the bloodstream. Achieving a balance between solubility and permeability is often challenging, as a compound that is highly water-soluble tends to be poorly fat-soluble, and vice-versa.
Molecular size and weight also play a significant role, as larger molecules generally exhibit lower permeability across the intestinal barrier. The chemical stability of the compound is also important, as it must resist degradation by the acidic environment of the stomach and digestive enzymes. The Biopharmaceutics Classification System (BCS) categorizes compounds based on their solubility and permeability, providing a framework for predicting absorption potential. For example, a Class IV drug, having both low solubility and low permeability, presents the greatest challenge for achieving adequate oral bioavailability.
Physiological and External Modifiers
The body’s physiological processes and external factors significantly modify the absorption process. Primary among these is first-pass metabolism, or presystemic metabolism, which can drastically reduce the amount of active substance reaching the systemic circulation. After absorption from the small intestine, the blood passes directly to the liver via the portal vein, where liver enzymes, primarily from the Cytochrome P450 family, begin to break down the compound. This mechanism is so effective for some drugs, such as nitroglycerin, that they must be administered by non-oral routes to bypass the liver’s initial processing.
Conditions within the gastrointestinal (GI) tract are highly variable and directly impact dissolution and absorption. The pH level is particularly influential, as the stomach is highly acidic (pH 1.0–3.0), while the small intestine is more neutral (pH 5.0–6.5). Weakly acidic drugs dissolve better in the higher pH of the intestine, while weakly basic drugs require the acidic environment of the stomach for dissolution. Changes in gastric emptying rate and intestinal transit time also affect bioavailability by determining the duration a substance remains at its optimal absorption site.
The gut microbiota, the community of microorganisms in the intestine, acts as a metabolic organ that can activate or deactivate compounds. These bacteria possess enzymes capable of breaking down drugs or nutrients into metabolites, sometimes resulting in a more active form, and other times leading to deactivation. Food and dietary interactions also introduce a variable, particularly through the food matrix effect. Consuming a substance with food can either enhance its absorption, often by stimulating bile acid secretion, or inhibit it by trapping the substance within the physical structure of the meal.
The pharmaceutical formulation itself is a powerful external modifier designed to manipulate how a substance is released. Immediate-release (IR) formulations dissolve quickly to provide a rapid peak concentration but require more frequent dosing. Extended-release (ER) or sustained-release formulations use specialized coatings or matrix systems to slow the release of the active compound. This maintains a more consistent concentration in the bloodstream and allows for less frequent dosing. Delayed-release (DR) products, often enteric-coated, are designed to remain intact in the stomach’s acid and only dissolve once they reach the higher pH of the small intestine.
Quantifying Bioavailability: Measurement Techniques
Scientists determine the value of bioavailability through pharmacokinetic (PK) studies that measure drug concentration in the blood over time. Absolute bioavailability is calculated by comparing the area under the plasma concentration-time curve (AUC) after non-intravenous (non-IV) administration, typically oral, to the AUC obtained after an intravenous (IV) injection. Since an IV dose delivers 100% of the active substance directly into the systemic circulation, it serves as the reference point. The resulting ratio, expressed as a percentage, indicates the fraction of the non-IV dose that successfully reached the bloodstream.
Relative bioavailability is used when comparing two different formulations of the same drug, such as a new tablet versus an existing capsule, without using an IV reference. This comparison is often performed to ensure that a generic drug is equivalent to a brand-name drug, a concept known as bioequivalence. Key parameters extracted from the plasma concentration-time curve include the maximum concentration (\(\text{C}_{\text{max}}\)), which represents the highest drug level achieved in the blood, and the time to maximum concentration (\(\text{T}_{\text{max}}\)), which indicates how quickly the substance is absorbed. The AUC reflects the total amount of active substance that entered the body’s circulation, serving as the measure of the extent of bioavailability.