### Definition/Introduction

Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination(s). More accurately, bioavailability is a measure of the rate and fraction of the initial dose of a drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug’s intended targets have unimpeded access.[1][2][3] For majority purposes, bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered. This definition assumes 100% of the active drug that enters systemic circulation will successfully reach the target site.[4] However, it should be appreciated that this definition is not inclusive of drugs that do not require access to systemic circulation for function (i.e., certain topical drugs). The bioavailability of these drugs is measured by different parameters discussed elsewhere.[2]

Bioavailability is an integral part of the pharmacokinetics paradigm. Pharmacokinetics is the study of drug movement through the body and is often represented by the acronym ABCD which stands for administration, bioavailability, clearance, and distribution. Administration refers to the route and dosing of a drug. Clearance is the active form of a drug being removed from the systemic circulation. Distribution measures how widely a drug can travel to fluid compartments of the body; this definition assumes distribution follows absorption if taken orally.[5]

The route of administration (ROA) and the dose of a drug have a significant impact on both the rate and extent of bioavailability. The dose of a drug is indirectly proportional to its bioavailability (Equation 5). For a drug with relatively low bioavailability, a larger dose is required to reach the minimum effective concentration threshold. The various routes of administration each contain a unique capability to facilitate a certain plasma drug concentration for a certain length of time. In many cases, altering the route of administration calls for an alteration of the dosage. For example, an oral drug requires passage through the gastrointestinal (GI) system, which would make it subject to intestinal absorption and hepatic first-pass metabolism.[4] On the contrary, an intravenously delivered drug (IV drug) is assumed to be immediately delivered to the systemic circulation. It does not require consideration of absorption or first-pass metabolism to determine adequate dosage.

Drug clearance can be thought of as the metabolic and excretory factors on the rate and extent an active drug leaves the systemic circulation. Clearance is measured by the drug elimination rate divided by the plasma drug concentration. The drug elimination rate is classically categorized into a binary system. A drug is eliminated either by first-order or zero-order kinetics. In zero-order kinetics, a constant amount of a drug is eliminated over time regardless of plasma concentration. However, zero-order kinetics implies absorption and elimination can become saturated, potentially leading to toxicity. In first-order kinetics, a constant fraction of the drug is eliminated over a period of time via the intrinsic half-life of the drug. Further, first-order drug elimination is exponentially proportional to plasma concentration (unlike zero-order kinetics). This implies that drug elimination will be exponentially higher when there is a higher plasma concentration of the drug. Therefore, providers should appreciate which category of elimination the drugs they prescribe follow, as this will affect drug clearance and bioavailability. For drugs following first-order kinetics, accumulation can occur if doses are delivered too frequently. This could result in unintended supratherapeutic consequences and side effects.[6] Together, bioavailability and clearance can be used to determine the steady-state concentration of a drug.[5] Steady-state concentration is the time frame in which the concentration of a drug in the plasma is constant. This occurs when the rate of a drug reaching systemic circulation is equal to the rate a drug is removed from the systemic circulation.[6] Thus, disparities in factors that affect the bioavailability of respective drugs are important to consider when assessing therapeutic efficacy. Factors that alter drug clearance will reliably alter bioavailability and steady-state concentration. Such is the case in renal diseases that perturb the kidneys’ ability to eliminate drugs in the urine. Any degree of failure to eliminate a drug may augment its bioavailability by maintaining a larger drug plasma concentration than would normally be expected over time.

In contrast with bioavailability which measures the rate and extent an active drug reaches the plasma of systemic circulation, distribution is a measure of the rate and extent a drug is delivered to the various compartments of the body; total body water, intracellular volume, extracellular volume, plasma volume, and blood volume. Drugs that are capable of venturing into multiple fluid compartments are considered in a multi-compartment model of distribution. Drugs that are thought to immediately distribute to their target domains, and do not normally distribute to peripheral compartments, are considered part of the single-compartment model. In the single-compartment model, any reduction in plasma drug concentration is assumed to have resulted from drug elimination.[7] The multi-compartment model is useful for tracking drug flow throughout the fluid compartments. In the context of both models, distribution is referred to as the volume of distribution (Vd) since volume is a convenient metric to compartmentalize the distribution of solutes, including drugs. The volume of distribution can be an important indicator of changes in bioavailability. The volume of distribution can be determined instantaneously by the proportion of the total amount of a drug in the body compared to the plasma concentration of the drug at a given time (Equation 1):[7]

**Equation 1:** *Vd = total amount of drug in the body ÷ plasma drug concentration*

Extrapolating from the equation, a drug with a larger Vd will have a larger distribution outside of the central compartment (plasma systemic circulation). It is important to consider how the relative breadth of a drug’s volume of distribution might affect the drug’s potential bioavailability. To illustrate, a drug that readily flows across multiple compartments may not be ideal if the intention is to maximize the plasma drug concentration.

Tacit in how bioavailability is classically defined is that an intravenously administered active drug that is delivered directly into systemic circulation yields a bioavailability of 100%. The bioavailability (F) of a drug delivered via other routes of administration can be determined by the mass of the drug delivered to the plasma divided by the total mass of the drug administered (Equation 2):

**Equation 2: ***F = mass of the drug delivered to the plasma ÷ total mass of the drug administered*

In pharmacologic contexts, an area under the curve graph (AUC) plots the plasma concentration of a drug on the y-axis versus time following drug administration on the x-axis (example shown in Figure 1).[8] The area under the curve is directly proportional to drug absorption. Recall that the bioavailability of any drug delivered intravenously is theoretically 100%, or 1. This allows for convenient calculation of the bioavailability of drugs not delivered intravenously. By dividing the area under the curve of a drug delivered orally, for example, by the area under the curve for the same dose of that same drug delivered intravenously, one may successfully calculate the bioavailability of the oral drug.[9]

Bioavailability can be derived from an area under the curve (AUC) graph (Equation 3), which can be observed in the associated Figure 1**.**[4] For clinical purposes, it is important to understand an AUC graph conceptually.

**Equation 3:** F = *AUC for X route of administration ÷ AUC for IV administration*

Thus, bioavailability is measured on a continuous range from 0 to 1 but can be represented as a percentage.[4] If it helps, “F” can be thought of as “fraction” because bioavailability is a non-IV drug’s AUC dividing into its IV version.