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Drug Bioavailability

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Last Update: October 20, 2020.

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 breach 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.

Issues of Concern

Limitations of current theoretical models of bioavailability do exist. It is worth noting that calculating bioavailability using AUC data assumes a constant drug clearance and a uniformly distributed concentration of the drug once it reaches the plasma. In all other cases, AUC data is unreliable.[10]

Oral drugs, unlike drugs with other ROAs (i.e., IV drugs), must undergo intestinal absorption and hepatic first-pass metabolism.[4] A myriad of structural and physiological gastrointestinal (GI) alterations such as GI surgery or chronic inflammatory intestinal conditions affect this absorption, typically by reducing bioavailability.[11] Genetic polymorphisms of intestinal transporters that facilitate absorption (i.e., P-glycoprotein 1) also affect drug bioavailability.[12] Verapamil, a calcium channel blocker that inhibits P-glycoprotein, has been shown to augment the plasma concentration of immunosuppressive drugs that utilize P-glycoprotein in their elimination, such as cyclosporine and tacrolimus, increasing the risk for toxicity.[13]

Following drug absorption into the intestines, drugs are delivered to the liver via the portal system. The liver is the site of first-pass metabolism. The bioavailability of a drug will be reduced proportionally to the fraction of the initial dose converted to inactive metabolites by liver enzymes.[14] Notably, hepatic cytochrome P450 metabolism can significantly alter drug bioavailability.[15] Cytochrome P450 enzymes can be inhibited or augmented by a concurrent drug, supplement, or food metabolism. Even non-prescription drugs have been demonstrated to interact with cytochrome P450 enzymes. The herbal drug St. John’s wort used most commonly for depression has been shown to increase cytochrome P450 activity, reducing the plasma concentration, and therefore bioavailability, of other drugs (i.e., warfarin) that are also metabolized by cytochrome P450 enzymes.[16] These observed interactions have implications for the importance of providers to inquire about supplements, over-the-counter (OTC) medications, and herbal drugs their patients are taking. Depending on interactions between the unique, temporal portfolio of substances and the target drug, bioavailability may be reduced or enhanced. Consideration of these interactions is critical in the prevention of undesirable clinical outcomes.

Clinical Significance

The bioavailability of a drug can be influenced by both intrinsic and extrinsic variables. Intrinsically, a drug’s bioavailability can be affected by the drug’s required metabolic steps to activation, the specificity of its target receptors, the patient’s unique physiology (including phenotypic polymorphisms), route of administration of the drug, and site of drug absorption. Extrinsic variables affecting drug bioavailability include interactions with concurrent food or substance metabolic processes and drug interactions with medications.[17]

A common clinical experience where an appreciation for bioavailability becomes important is the interactions between warfarin and albumin in the plasma. Warfarin has a propensity for binding with human serum albumin. Albumin-warfarin binding inactivates warfarin and reduces the fraction of active, free warfarin in the systemic circulation. When albumin hoards warfarin in the blood, both the clearance and bioavailability of warfarin is reduced.[18] It may be necessary to restate that bioavailability refers to the fraction of active drug concentration in the plasma; albumin-bound warfarin is not an active form of warfarin. This phenomenon implies the monitoring of serum albumin and dietary choices (especially in regard to protein) when evaluating an adequate warfarin dose to prevent toxicity or inefficacy.

The use of nitroglycerin in angina relief is another common clinical example that illustrates how differences in routes of administration with disparate bioavailabilities can affect clinical outcomes. Nitroglycerin delivered orally will be affected by the first-pass metabolism in the liver, reducing the rate and extent of the drug that reaches its target sites. In consequence, the therapeutic effect of oral nitroglycerin should be slower in development and more sustained. For these reasons, oral nitroglycerin is commonly prescribed to patients with coronary artery disease for prophylactic use.[19]

In contrast, oral administration of nitroglycerin might not be the most appropriate route of administration for the immediate relief of angina. Sublingual nitroglycerin diffuses immediately into the bloodstream, bypassing intestinal absorption and first-pass metabolism. Consequently, its therapeutic effects are manifested as early as 2 minutes, yet last only 10-15 minutes in duration.[20] This is the rationale for the common use of sublingual nitroglycerin to provide more immediate relief of anginal chest pain. Intravenous nitroglycerin can be used when the sublingual administration fails.[19]

Fortunately, many AUC and bioavailability data have been previously calculated in pharmacokinetic studies, which are available to providers. The clinical pearl here is being able to use these numbers to make pharmacologic decisions such as dosage and schedule.

Factors such as dose (D), route of administration, bioavailability (F), and total clearance (CT) will affect AUC.[4] Accommodations for changes in these variables can be made with relatively simple calculations (Equation 4).[4]

Equation 4: AUC = (F x D) ÷ CT

Understanding bioavailability is important for the clinician to determine the most appropriate route, schedule, and dose of administration, a drug should be delivered in specific clinical scenarios. Bioavailability is integral in evaluating an appropriate loading and maintenance dose. The loading dose is part of the initiation of treatment and is typically higher than the maintenance dose. It is intended to frontload an adequate plasma drug concentration that will be subsequently maintained by the maintenance dose. If the volume of distribution (Vd), desired steady-state concentration (Css), and bioavailability (F) are known, one can calculate the loading dose (LD) using Equation 5. If the desired steady-state concentration (Css), dosing interval (DI), bioavailability (F), and clearance (CL) are known, the maintenance dose (MD) can be determined (Equation 6).[7]

Equation 5: LD = (Css x Vd) ÷ F

Equation 6: MD = (Css x CL x DI) ÷ F

Prescribing doses that are most appropriate for the clinical scenario is critical to patient outcomes. For example, an antimicrobial dose that cannot maintain a plasma concentration within the therapeutic window could fail to treat a patient’s infection and possibly contribute to antimicrobial resistance. Conversely, prescribing a dose too high could result in toxicities idiosyncratic to that drug. When considering the administration of a drug, it is imperative to appreciate the relevance of bioavailability in each drug and patient interaction.

Nursing, Allied Health, and Interprofessional Team Interventions

As the diversity of drug delivery continues to expand to accommodate patient needs, the risk of prescribing errors will increase. Nuanced differences between medication labels or different doses of the same drug with different routes of administration can be an ignition for human error. In the most objective sense, the physiologic manifestation of these errors can be traced to aberrant changes in basic pharmacokinetic principles. A focus on bioavailability can serve as a logical hinge to consider drug-patient and drug-drug interactions.

The first step toward mitigating medical errors associated with bioavailability is a shared knowledge of the basic principles of bioavailability between members of the interprofessional team caring for the patient. Including this knowledge as part of staff training can be fruitful. Nurses with an augmented appreciation for bioavailability can use the patient’s history, vitals, and medication list more effectively and become another barrier to adverse drug events (ADEs). This knowledge may provide additional confidence to nurses executing drug administrations to patients.

With more opportunities for medical mistakes, the impetus falls on creating and maintaining a system that mitigates these mistakes as best possible. Avid communication among members of the interprofessional team can significantly reduce the risk of prescription errors. Utilizing pharmacists regularly in pharmaceutical decision support has been shown to effectively reduce the risk of adverse drug events.[21] [Level 3]. When opportunity allows, pharmacists can perform a medication order review before drug administration. Pharmacist review is yet another barrier to adverse drug events because their more detailed pharmaceutical expertise is well-equipped for surveying a wider scope of potential drug interactions.

After drug administration, scheduled checkpoints for patient monitoring can provide a safety net for unanticipated pharmacologic responses. One important checkpoint is obtaining laboratory values at regular intervals. It is a safety measure to ensure a prescribed drug is maintained within the therapeutic range. In addition to ensuring drug efficacy through adequate plasma drug concentration, this checkpoint can serve as a method to prevent drug accumulation and toxicity. Between these intervals, checking patient vitals more frequently in patients with complex illnesses and medication lists is a useful method in monitoring acute physiologic reactions secondary to changes in drug bioavailability.

Ultimately, obtaining and recording a complete medical history is critical in forming the breadth of medical background required to make safer prescription decisions. A previous study showed that 61% of patients (n=304) have one or more prescriptions not recorded.[22] [Level 3] This inadequacy reveals a significant vulnerability to patients in the context of potential adverse drug events. Further, nonprescription drugs, herbal supplements, and food products have capabilities of altering drug bioavailability; such is the essence of extraordinary dietary monitoring of patients taking warfarin.[18] While augmented interprofessional teams can mitigate bioavailability-associated adverse patient outcomes, the systems themselves are limited to the degree of medical and lifestyle knowledge known about the patient and the drugs they take.

Continuing Education / Review Questions

Area under the curve (AUC) graph example

Figure

Area under the curve (AUC) graph example. Contributed by Thierry Buclin, MD and Marc Sohrmann, PhD

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