Introduction to Pharmacokinetics

Pharmacokinetics (PK) is a critical field of study that examines how the body interacts with administered substances, particularly medications, throughout the duration of exposure. This branch of pharmacology is closely related to, but distinct from, pharmacodynamics, which focuses on the drug’s effect on the body. Pharmacokinetics primarily investigates four key parameters: absorption, distribution, metabolism, and excretion (ADME).[1]


Understanding these processes is essential for practitioners to prescribe and administer medications that provide the greatest benefit at the lowest risk while also allowing them to make necessary adjustments based on the diverse physiology and lifestyles of patients. This article will delve into the fundamental concepts of pharmacokinetics, their clinical significance, and the role of the interprofessional team in optimising patient outcomes.

Absorption: The Gateway to Systemic Circulation

Absorption is the process by which a drug moves from its site of administration, such as a tablet or capsule, into systemic circulation. The speed and concentration at which a drug reaches its desired location of effect, such as plasma, are influenced by absorption. There are numerous methods of drug administration, including oral, intravenous, intramuscular, intrathecal, subcutaneous, buccal, rectal, vaginal, ocular, otic, inhaled, nebulized, and transdermal, each with its own absorption characteristics, advantages, and disadvantages.1

The absorption process often involves liberation, which is the release of the drug from its pharmaceutical dosage form. This is particularly important for oral medications, as they may be delayed in the throat or oesophagus for hours after administration, potentially delaying the onset of effects or causing mucosal damage. Once in the stomach, the low pH environment may initiate chemical reactions with these drugs before they even reach systemic circulation.[1]

Bioavailability: Quantifying the Fraction of Drug in Circulation

Bioavailability refers to the fraction of the originally administered drug that reaches the systemic circulation, and it is dependent on the properties of the substance and the mode of administration. Bioavailability is a direct reflection of medication absorption. For example, when a medication is administered intravenously, 100% of the drug enters circulation almost instantly, resulting in a bioavailability of 100%. This makes intravenous administration the gold standard for bioavailability, and it is particularly relevant for orally administered medications.[2]

Oral medications must navigate the acidic environment of the stomach and be absorbed by the digestive tract. Digestive enzymes begin the process of metabolism for oral drugs, reducing the amount of drug that reaches circulation even before absorption occurs. Once absorbed by gut transporters, the medications often undergo “first-pass metabolism,” where they are processed in large quantities by the liver, gut wall, or digestive enzymes, further lowering the amount of drug that reaches circulation and resulting in a lower bioavailability.[2]

To account for the varying dissemination characteristics of different modes of administration, such as intramuscular, oral, or transdermal, the area under the plasma concentration curve (AUC) is used. The AUC calculates the drug bioavailability by observing the plasma concentration over a given time. By calculating the integral of that curve, bioavailability can be expressed as a percentage of the 100% bioavailability achieved through intravenous administration.

Distribution: Spreading the Drug Throughout the Body

Distribution describes how a substance is spread throughout the body, which varies based on the biochemical properties of the drug and the physiology of the individual taking the medication. In the simplest sense, distribution may be influenced by two main factors: diffusion and convection.[3]

These factors can be affected by the polarity, size, or binding abilities of the drug, the fluid status of the patient (hydration and protein concentrations), or the body habitus of the individual.[4] The goal of the distribution is to achieve the effective drug concentration, which is the concentration of the drug at its designed receptor site. For a medication to be effective, it must reach its designated compartmental destination, described by the volume of distribution, and not be protein-bound to be active.

Volume of Distribution (Vd): Quantifying Drug Dissemination

The volume of distribution (Vd) is a common method of describing the dissemination of a drug. It is defined as the amount of drug in the body divided by the plasma drug concentration.[4] The body consists of several theoretical fluid compartments (extracellular, intracellular, plasma, etc.), and Vd attempts to describe the fictitious homogenous volume in a theoretical compartment.

When a molecule is very large, charged, or primarily protein-bound in circulation, such as the GnRH antagonist cetrorelix (Vd = 0.39 L/kg), it remains intravascular, unable to diffuse, which is reflected by a low Vd. In contrast, a smaller and hydrophilic molecule would have a larger Vd, indicating its distribution into all extracellular fluid. Finally, a small lipophilic molecule, such as chloroquine (Vd = 140 L/kg), would have a very large Vd as it can distribute throughout cells and into adipose tissues.[5] There may be multiple volumes of distribution depending on the rate of distribution within the subject.[4]

Understanding the volume of distribution is crucial for practitioners to determine appropriate dosing schemes. For example, an individual with an advanced infection may require a loading dose of vancomycin to achieve desired trough concentrations. A loading dose allows the drug concentrations to rapidly reach their ideal concentration instead of needing to accumulate before becoming effective. Loading doses are directly related to the volume of distribution and are calculated by multiplying Vd by the desired plasma concentration and dividing by bioavailability.[6]

Protein Binding: The Role of Free and Bound Drug

In the body, a drug may be protein-bound or free. Only free drugs can act at their pharmacologically active sites, such as receptors, cross into other fluid compartments, or be eliminated. In the clinical setting, the free concentration of a drug at receptor sites in plasma more closely correlates with the effect than the total concentration in plasma.[4] The protein binding of the substance largely determines this. Any reduction in plasma protein binding increases the amount of drug available to act on receptors, possibly leading to a greater effect or an increased possibility of toxicity. The principal proteins responsible for binding medications of interest are albumin and alpha-acid glycoprotein.[7]

Protein binding may fluctuate depending on the age and development of the patient, any underlying liver or kidney disease, or nutrition status. One example in which this is relevant is renal failure. In renal failure, uremia decreases the ability of acidic drugs, such as diazepam, to bind to serum proteins. Even though the same amount of drug is initially given, there is far more drug in the “active” space, unbound by serum protein. This will increase the effect of the medication and increase the possibility of toxicity, such as respiratory depression.[4]

Metabolism: Processing Drugs in the Body

Metabolism is the process by which the body processes a drug into subsequent compounds. This is often used to convert the drug into more water-soluble substances that will progress to renal clearance or, in the case of prodrug administration, such as codeine, metabolism may be required to convert the drug into active metabolites.[8]

Different strategies of metabolism may occur in multiple areas throughout the body, such as the gastrointestinal tract, skin, plasma, kidneys, or lungs, but the majority of metabolism occurs through phase I (CYP450) and phase II (UGT) reactions in the liver. Phase I reactions generally transform substances into polar metabolites by oxidation, allowing Phase II conjugation reactions to occur.[2] Most commonly, these processes inactivate the drug, convert it into a more hydrophilic metabolite, and allow it to be excreted in the urine or bile.

Excretion: Eliminating Drugs from the Body

Excretion is the process by which the drug is eliminated from the body. The kidneys most commonly conduct excretion, but for certain drugs, it may occur via the lungs, skin, or gastrointestinal tract. Medications may be cleared in the kidneys by passive filtration in the glomerulus or secretion in the tubules, complicated by reabsorption of some compounds.

Clearance: Quantifying Drug Elimination

Clearance is an essential term when examining excretion; it is defined as the ratio of a drug’s elimination rate to the plasma drug concentration. This is influenced by the drug and the patient’s blood flow and organ status (usually kidneys). In the perfect extraction organ, in which blood would be completely cleared of medication, the clearance would become limited by the overall blood flow through the organ.[4]

Understanding clearance allows practitioners to calculate appropriate dosing rates for medications. Maintenance dosing ideally replaces the amount of drug eliminated since the previous administration.[9] Maintenance doses are calculated by multiplying clearance by the desired plasma concentration and dividing by bioavailability.

Half-life (t): The Time for Drug Concentration in Serum/Plasma to Decrease by 50%

The half-life is the amount of time it takes for serum drug concentrations to decrease by 50%. Defined by the equation t=(0.693xVd)/Clearance, a drug’s half-life is directly proportional to the volume of distribution and inversely proportional to clearance. The half-life of medications often becomes altered by changes in the clearance parameters that come with disease or age.[4,10]

Drug Kinetics: Graphical Representation of Metabolism and Excretion

Drug kinetics is the graphical manifestation of metabolism and excretion and depicts a medication’s half-life. The two major forms of drug kinetics are described by zero-order versus first-order kinetics.

Zero-order kinetics display a constant rate of metabolism and/or elimination independent of the concentration of a drug. This is the case with alcohol and phenytoin elimination. There is a variable half-life that decreases as the overall serum concentrations decrease. In contrast, first-order kinetics relies on the proportion of the plasma concentration of the drug. First-order kinetics has a constant half-life with decreasing plasma clearance over time. This is the major elimination model for most medications.

These two models are not usually independent for most drugs. However, as is the case with salicylates, at concentrations below 1.4 mmol/L, elimination is proportional to serum concentrations, while at higher concentrations, elimination is constant due to saturation of metabolic and eliminatory processes.[11]

These kinetic models can be used to estimate steady states and the complete elimination of medications. A steady state is when the administration of a drug and the clearance are balanced, creating a plasma concentration that is unchanged over time. Under ideal treatment circumstances, when a drug is administered by continuous infusion, this is achieved after treatment has been operational for four to five half-lives. This is the point at which the system is said to be in a steady state. This steady-state concentration can only be altered by changes in dosing interval, total dose, or changes in the clearance of the drug.

Similarly, total elimination is measurable by half-lives. Upon administration of a drug that follows first-order elimination kinetics, it may be assumed that it is completely eliminated by four to five half-lives, as by that point, 94 to 97% of the medication has left the system. For example, the half-life of morphine is 120 minutes; therefore, one may assume that there is a negligible amount of morphine in a patient’s system eight to ten hours after administration.[12]

Clinical Significance of Pharmacokinetics

When a provider prescribes medication, the ultimate goal is to achieve a positive therapeutic outcome while minimising adverse reactions. A thorough understanding of pharmacokinetics is essential in building treatment plans involving medications. Pharmacokinetics, as a field, attempts to summarise the movement of drugs throughout the body and the actions of the body on the drug. By using the above terms, theories, and equations, practitioners can better estimate the locations and concentrations of a drug in different areas of the body.

The appropriate concentration needed to obtain the desired effect and the amount required for a higher chance of adverse reactions are determined through laboratory testing. Using the equations discussed, a clinician can easily estimate safe medication dosing over time and how long it will take for a drug to leave a patient’s system.

However, it is important to note that these are statistically-based estimations influenced by differences in the drug dosage form and patient pathophysiology. This is why a deep understanding of these concepts is essential in medical practice, making improvisation possible when the clinical situation requires it.

Interprofessional Team Interventions

The interprofessional team members caring for the patient need to work together to ensure the safety and efficacy of pharmacotherapy. The patient may require training on correctly self-administering and storing their medications. The physician, nurse, or pharmacist can perform this education. It may serve the patient well to hear this information from multiple providers to optimise therapy and minimise toxicity.

Notably, the interprofessional team needs to monitor for signs of drug efficacy and toxicity, which are affected by the drug’s pharmacokinetic parameters, such as half-life. The pharmacist should verify the dosing, perform a drug interaction check, and follow the plasma concentrations of medication if clinically warranted, such as with gentamicin. Nurses can monitor adverse events, make preliminary assessments of treatment effectiveness on subsequent visits, and verify patient medication adherence.

Both nurses and pharmacists need to have an open communication line with the prescribing physician to report or discuss any concerns regarding drug therapy or the patient’s drug regimen in general. This type of interprofessional communication is necessary to optimise patient outcomes with minimal adverse events.[13] [Level 5]


Pharmacokinetics is a crucial field of study that examines how the body interacts with administered substances, particularly medications, throughout the duration of exposure. Understanding the key parameters of absorption, distribution, metabolism, and excretion is essential for practitioners to prescribe and administer medications that provide the greatest benefit at the lowest risk, while also allowing them to make necessary adjustments based on the diverse physiology and lifestyles of patients.

By grasping the concepts of bioavailability, volume of distribution, protein binding, clearance, half-life, and drug kinetics, clinicians can better estimate the locations and concentrations of a drug in different areas of the body and determine appropriate dosing schemes. However, it is important to recognize that these are statistically-based estimations influenced by differences in the drug dosage form and patient pathophysiology, highlighting the need for a deep understanding of these concepts in medical practice.

The interprofessional team plays a vital role in ensuring the safety and efficacy of pharmacotherapy by providing patient education, monitoring for signs of drug efficacy and toxicity, verifying dosing and drug interactions, and maintaining open communication among team members. This collaborative approach is essential for optimising patient outcomes and minimising adverse events.

In conclusion, a thorough understanding of pharmacokinetics is crucial for healthcare professionals to provide the best possible care for their patients. By applying the principles of pharmacokinetics and working together as an interprofessional team, clinicians can ensure that medications are prescribed and administered in a manner that maximises therapeutic benefits while minimising the risk of adverse reactions.


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Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.

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