The bioavailability of a drug is the fraction of the administered dose that reaches the systemic circulation. For example, the bioavailability of an intravenous injection is 100% (Birkett, 2003), whereas bioavailability will vary for other routes of administration depending on factors that affect the extent of absorption into the circulatory system and first-pass hepatic metabolism. The measurement that determines absolute bioavailability is called the area under the curve (AUC). This measurement is determined by calculating the AUC of the plasma concentration plotted over time (Birkett, 2003) (Figure 7-2).

The bioavailability of a specific drug is the determinant of the dosage and is equivalent to the drug administered via various routes of administration. For example, chronic use of morphine administered orally has a bioavailability of around 20% to 30% of the parenteral dose (100% bioavailability) (Doyle, Hanks, Cherny et al., 2005). This means that a patient who has been receiving 10 mg of morphine intravenously will require approximately 30 mg of morphine orally to achieve the same analgesic effect as experienced from the intravenous dose (American Pain Society, 2003).

Drugs are considered bioequivalent when the extent and rate of absorption are similar and there is no difference between the therapeutic and adverse effects. A generic drug company, for example, that manufactures a drug in the same dosage form as a brand-name product will often use the AUC bioavailability data when comparing the two drugs. For a generic drug to be considered equivalent to the brand drug, the bioavailability must be similar to that of the brand product (USDHHS-FDA, 2006). The Electronic Orange Book is an online publication of the U.S. Department of Health and Human Services Food and Drug Administration that lists approved drug products and their therapeutic equivalence evaluations.

Therapeutic range is defined as the plasma concentration that occurs between the concentration of drug needed to achieve the desired pharmacological effect and the concentration where adverse effects are observed (Figure 7-3). For some drugs, this range is narrow, and for other drugs, it is wide. The narrower the range, the more monitoring is needed to prevent adverse drug effects or clinical misadventures. Some monitoring is done based on plasma drug concentrations (e.g., gentamicin, theophylline, and digoxin). Other drug monitoring is done by measuring physiological changes that are caused by the drug (e.g., measuring international normalized ratio for Coumadin [warfarin] and thyroid-stimulating hormone for levothyroxine).

Once the drug is absorbed into the systemic circulation, it is distributed throughout the body. The apparent volume of distribution (V _D) is a measure of where the drug goes once it is completely distributed throughout the body (Table 7-2). It is the ratio of the fraction of drug unbound to protein in the plasma to the fraction of unbound drug in the tissue, and it is expressed as liters per kilogram (L/kg). The volume of distribution is also determined by the strength of binding of the drug to plasma proteins in relationship to the strength of binding to tissue components. If a drug is highly bound by tissue and not by blood, it will allow most of the drug to be held in the tissues of the body and little will be held within the blood. In this case, the drug will have a large volume of distribution. The V _D is measured by plotting the logarithm of the plasma concentration against time. The result is a straight line that can be extrapolated back to zero (Birkett, 2003). The plasma concentration at zero time (C ₀) divided by the dose equals the volume of distribution:

A loading dose (LD) can be used when attempting to achieve a rapid concentration of a specific drug. The volume of distribution is the pharmacokinetic parameter used when calculating an LD of a drug. For example, if a drug has a V _D of 40 liters (L) and the desired concentration (c) is 10 mg/L, then a loading dose to achieve that concentration is 400 mg:

It is important for the clinician to understand that the administration of an LD will decrease the time it takes to achieve a desired concentration and will not decrease the time it takes to reach steady-state (Birkett, 2003).

The half-life ( t_1/2) is identified by the time it takes for the plasma concentration and the amount of drug within the body to fall by half after it has undergone absorption and distribution. Half-life is the reciprocal function of the elimination rate constant. The half-life and elimination rate constant are determined by both clearance (CL) and V _D (Urso, Blardi, & Giorgi, 2002) (Figure 7-4). Half-life determines the duration of action after a single dose of a drug and the amount of time required to reach steady state with constant dosing.

The therapeutic concentration range, also known as the therapeutic window, is the drug concentration range where most patients will have a therapeutic effect with the least amount of adverse effects. In general, the usual therapeutic range and drug effect are proportional to the logarithm of drug concentration. Therefore, drug effect after a single dose usually declines in a linear relationship over time. Notwithstanding, a number of mechanisms result in a dissociation of the usual relationship between drug concentration and effect. Changes in volume of distribution due to dehydration of overhydration and changes in renal or liver function are examples of factors that will affect the drug concentration–and–effect relationship.

Steady state occurs when the rate of drug administered is equal to the rate of elimination from the body. It generally takes three to five drug half-lives to reach steady state. For example, when immediate-release morphine ( t_1/2 ≈4 hours) is administered routinely every 4 hours, steady state is achieved within 24 hours. For a drug with a longer half-life, such as methadone ( t_1/2 ≈20 to 35 hours), steady state is achieved in approximately 6 to 10 days (Lugo, Satterfield, & Kern, 2006).

Drug concentrations are often measured as unbound plasma drug concentrations rather than as whole blood concentrations. With oral and intermittent dosing, once the steady state has been achieved, despite a fluctuation in drug doses, the amount of drug administered will equal the amount of drug eliminated. This results in an average drug concentration that is equal to an intravenous infusion (Olson, 2003).

With intermittent dosing, when the dosing interval is equal to the half-life of the drug, the result is about a two-fold fluctuation in drug concentration over the dosing interval. In cases where the drug is administered orally and at an interval that is not equal to the drug’s half-life, the degree of plasma concentration fluctuation over the dosing interval is determined by both the absorption rate and the relationship of the dosing interval to the half-life. Although a drug may be at steady state, if the dose is changed, it again will take three to five half-lives to reach a new steady state. Conversely, upon discontinuation of a dose, it takes four half-lives to eliminate 94% of the drug from the body (Birkett, 2003; Olson, 2003).

To achieve a sustained systemic blood level of medication that has a short half-life and a narrow therapeutic window, drugs are often formulated in an oral sustained-release matrix. Morphine is an example of a drug that is available in an immediate-release form (i.e., on administration, the entire dose is available to be absorbed and distributed to the site of action) and in a sustained-release format where systemic blood levels are available for 8, 12, and 24 hours after ingestion of a single-unit dose. When morphine is administered as an immediate-release dose, it is typically dosed at an interval close to its half-life (i.e., every 4 hours) to maintain a constant therapeutic systemic level. Sustained-release morphine has the same half-life and clearance as immediate-release morphine. The sustained-release matrix formulation is designed to gradually release drug, resulting in a fraction of morphine available for absorption and distribution. Consequently, altering the sustained-release matrix through crushing, for example, will destroy the delayed absorption property and result in a bolus of the entire dosage, leading to loss of a sustained serum concentration and potentially toxicity (Olson, 2003).

Medication clearance (CL) is the most important pharmacokinetic property of a drug. It is the measure of the efficiency of irreversible elimination of the drug from the systemic circulation and is expressed as the volume of blood cleared of unchanged drug per unit of time. Furthermore, it is the sum of drug clearance from systemic circulation, which includes the body’s vital organs. CL determines the steady-state concentration of a drug for a given dose rate.

However, if a drug is administered intermittently, as in the case of oral dosing, C _ss is determined by

where F is the fraction of the dose absorbed into the systemic circulation, D is the dose of the drug, and τ is the dosage interval.

It is important for the clinician to note that the clearance of a drug can be altered by several factors, including liver and kidney insufficiency, changes in protein and tissue binding, and the concomitant administration of other medications.

Once a drug is in the body, the process of elimination begins. The majority of drugs are eliminated by “first-order,” or linear, pharmacokinetics. This process of elimination is exponential or logarithmic (Figure 7-5). As an example of linear pharmacokinetics, when a dose is doubled from 200 mg/day to 400 mg/day, the patient’s serum drug concentration also doubles (Birkett, 2003).