Volume of Distribution


Article Author:
Asad Mansoor


Article Editor:
Navid Mahabadi


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
7/22/2019 11:32:26 AM

Definition/Introduction

The volume of distribution (Vd) is a pharmacokinetic parameter representing an individual drug’s propensity to either remain in the plasma or redistribute to other tissue compartments. By definition, Vd is a proportionality constant that relates the total amount of drug in the body to the plasma concentration of the drug at a given time.[1][2][3] The following equation can represent Vd:

Volume of Distribution (L) = Amount of drug in the body (mg) / Plasma concentration of drug (mg/L)

Based on the above equation:

  • A drug with a high Vd has a propensity to leave the plasma and enter the extravascular compartments of the body, meaning that a higher dose of a drug is required to achieve a given plasma concentration. (High Vd -> More distribution to other tissue)
  • Conversely, a drug with a low Vd has a propensity to remain in the plasma meaning a lower dose of a drug is required to achieve a given plasma concentration. (Low Vd -> Less distribution to other tissue)

Issues of Concern

General Principles Related to Drug Distribution

Pharmacokinetics focuses on drug movement throughout the human body via the processes of absorptiondistribution, and elimination. Upon administration, a drug moves from the site of administration and gets absorbed into the systemic circulation where it will then gets distributed throughout the body. The process of distribution refers to the movement of a drug between the intravascular (blood/plasma) and extravascular (intracellular & extracellular) compartments of the body. Within each compartment of the body, a drug exists in equilibrium between a protein-bound or free form. Over time, drugs within the circulation will then be metabolized and excreted from the body by the liver & kidneys.[1][3]

Single vs. Multi-compartment models of Distribution

Immediately after administration of an IV bolus, a drug enters the “central” compartment, which is composed of the plasma, highly perfused organs (liver, kidneys, etc.) and other tissues where drug distribution is instantaneous. Eventually, some drugs may begin to move from the central compartment to the “peripheral” compartment, which is composed of tissues to which drug distributes slower.[1][2][3][4]

  • Single compartment model: Some drugs display pharmacokinetics in which they distribute “instantaneously.” These drugs appear to remain in the central compartment and not distribute to peripheral compartments. Therefore, any measured decline in drug plasma concentration is a result of drug elimination from the body only. These drugs are said to display single-compartment models of distribution as they do not move to peripheral compartments. The Vd of these drugs can be represented by a single value, which is the Vd of the central compartment (Vc).[2][3]
    • Vc (L) = Dose administered (mg) / Co (mg/L)

Drugs that display single compartment distribution kinetics with a straight line graph on plasma vs. time curves. Because the drug is said to distribute instantaneously, the initial plasma concentration of drug at time = 0 (Co) is difficult to measure and is therefore estimated via extrapolation to time = 0 on a plasma concentration vs. time curve.[1][2][3]

  • Multi-compartment model: Most drugs will exhibit slower distribution kinetics, which involves an early distribution phase followed by a later elimination phase. Drugs that display multi-compartment models of distribution will move from the central compartment into peripheral compartments before elimination.[1][2][3][4][5] Phases associated with multi-compartment models of distribution include:
    • Distribution phase: following administration plasma drug concentration will initially decline while the total amount of drug in the body remains the same. This phenomenon will cause a single drug to have multiple Vd values, which are each time-dependent.
    • Terminal elimination phase: Following the distribution phase, the drug will be eliminated from the central compartment (by the kidneys/liver) causing changes in both amounts of the drug in the body and plasma drug concentration. Therefore, additional Vd values are calculable during the terminal elimination phase (Vbeta), which is a Vd value dependent on drug clearance.
    • Steady-state: Between the distribution & elimination phase, there is a transition point known as "steady state." Steady-state represents a period of “dynamic equilibrium” of a drug throughout the body in which the drug has completed distribution between the central & peripheral compartments. At steady state, the net flux of drug between the central & peripheral compartments is 0. Another value for Vd can be calculated during steady-state (Vss). This value is generally the most clinically relevant as it is used to determine the loading dose of a drug.
      • Vd (L) = A(t) (mg) / C(t) (mg/L)
        • A(t) represents the amount of drug in the body at time = t
        • C(t) represents plasma concentration of the drug at time = t

Drugs that display multiple compartment distribution kinetics have graphs that are biphasic lines on plasma vs. time curves.

Half-life and Volume of Distribution

Half-life (t1/2) refers to the time required for plasma concentration of a drug to decrease by 50%. t1/2 is dependent on the rate constant (k), which is related to Vd & clearance (CL).[1][2][3] Half-life can be expressed using the following equation(s):

  • Half-life (hours) = 0.693 x (Volume of distribution (L) / Clearance (L/hr))

Only the drug located in the central compartment can be eliminated from the body because the process of elimination is primarily carried out by the liver and kidneys. Drugs with a high Vd will have a large fraction of drug remaining outside of the central compartment. Meanwhile, the fraction of drug in the plasma will be eliminated, causing a shift of equilibrium resulting in drug located in the peripheral compartment to shift into the central compartment. This shift will cause the plasma concentration to remain at a steady-state concentration despite drug removal from the body. This phenomenon causes plasma concentration to decline more slowly during the elimination phase in the setting of a high Vd.[1][3]

Therefore, at a constant rate of clearance, a drug with a high Vd will have a longer elimination half-life than a drug with lower Vd. 

Similar to the different Vd values that exist depending on the pharmacokinetic phase, there are also two half-life values of which it is important to be aware:

  • The distribution half-life (t1/2a) which represents the amount of time required for the plasma concentration to decline by 50% during the distribution phase.
  • The elimination half-life (t1/2b) which represents the amount of time required for the plasma concentration to decline by 50% during the elimination phase. 

Features of Drugs affecting the Volume of Distribution

  1. Acid-Base Characteristics
    • As previously discussed, drugs may have a propensity to bind proteins throughout the body where they reach a point of equilibrium between a bound & unbound phase. Depending on the charge of a drug at physiologic pH, have a drug may tend to bind macromolecules inside or outside the plasma.[2]
      • Basic (alkaline) molecules have strong interactions with negatively charged phospholipid head groups located on phospholipid membranes. The extent of this binding is also dependent on the overall lipophilicity of the drug. In general, basic molecules will leave the systemic circulation leading to higher Vd as compared to acidic molecules.
      • Acidic molecules have a higher affinity for albumin molecules at lower lipophilicity than neutral or basic molecules. Therefore, acidic drugs are more likely to bind albumin and remain in the plasma leading to lower Vd as compared to more basic molecules.
  2. Lipophilicity
    • In addition to ionic/charge-related interactions between a drug and macromolecules, hydrophobic interactions also play a similar role. Drugs with higher lipophilicity have a higher lipid membrane permeability and therefore, a higher chance of leaving the plasma and interacting with other hydrophilic residues in the peripheral tissue (e.g., adipose tissue). However, plasma proteins such as albumin have a high affinity for lipophilic drugs in which case, the determinant of the extent of plasma protein binding of two equally lipophilic drugs is the acid/base characteristics as described above.[2] But in general, the following principles apply:
      • Lipophilic molecules are more likely to pass through lipid bilayers and therefore more likely to leave the bloodstream and distribute to areas with high lipid density (adipose) and therefore have a higher Vd.
      • Hydrophilic molecules are less likely to pass through lipid bilayers and therefore more likely to remain in the bloodstream and therefore have a lower Vd.

Clinical Significance

As previously discussed, multiple values of Vd can be calculated depending on the intrinsic drug kinetics (single vs. multiple compartment models) as well as the phase of drug kinetics following drug administration (distribution phase vs steady state vs terminal elimination phase). However, from the clinical perspective, the single most important utility of Vd is calculating the loading dose of a drug.[1][3]

The loading dose is best calculated using the Vd at steady state (Vss) as it is the most representative of the specific drugs pharmacokinetic properties at desired steady-state plasma concentration. Therefore, the loading dose can be calculated using the following equation:

  • Loading dose (mg) = [Cp (mg/L) x Vd (L)] / F
    • Cp represents the desired plasma concentration of drug 
    • Vd represents the volume of distribution
    • F represents the bioavailability of drug (IV administration = 1)

After administration of a loading dose, additional maintenance doses can be administered to maintain the desired plasma concentration of the drug. Unlike, the loading dose, which is dependent on the drug's Vd, the maintenance dose is dependent on clearance (Cl).[3] Maintenance dosing can be calculated with the following equation:

  • Maintenance dose rate (mg/hr) = [Cp (mg/L) x Cl (L/hr)] / F
    • Cp represents the desired plasma concentration of drug 
    • Cl represents the clearance rate of drug
    • F represents the bioavailability of drug (IV administration = 1)  

Key differences between loading doses & maintenance doses include:

  • The loading dose is contingent on the volume of distribution while maintenance doses are dependent on plasma clearance.[3]
  • The loading dose is only required for a few drugs in certain situations while maintenance doses are required for most drugs to maintain the steady-state plasma concentration.[3]
    • Loading doses are usually indicated in clinical scenarios where a drug needs to reach steady-state rapidly.
      • Ex, antiepileptic administration during an active seizure or aspirin loading during a suspected myocardial infarction
  • Loading dose rarely needs to be modified while maintenance doses need to be adapted depending on various characteristics of the patient.[3]
    • Because maintenance doses are dependent on drug clearance which is a variable dictated by each individual patient, maintenance doses are often variable as certain patients may take less or more time to clear a drug from the plasma.
      • E.g., renal failure patients will take longer to eliminate a drug in the urine. Therefore maintenance dose is corrected based on the patient's renal function. In these cases, the loading dose will remain the same, and the maintenance dose will undergo correction (decrease amount of drug per hour or increased time interval between doses).

Although drugs have inherent properties that govern the Vd, the patients also represent variables that can alter the apparent Vd. Therefore, the apparent Vd of certain drugs may vary significantly between patients depending on each patient’s individual physiology and/or pathophysiology. For example:

  1. Pediatric vs. adult dosing – Body composition changes with aging and therefore, drug distribution will be affected meaning that loading doses will vary between pediatrics and adults.[6]
  2. Obesity vs. Normal BMI –  The loading doses of drugs such as anesthetics may be dosed based on different weight scalars such as total body weight vs. ideal bodyweight depending on the pharmacokinetics of specific drugs to prevent over or underdosing.[7][8]
  3. Conditions affecting plasma protein concentration – The excess or deficiency of plasma proteins (e.g., albumin) may affect the amount of drug that remains in the plasma and therefore the apparent Vd.[1][5][9]

Understanding volume of distribution is important for both physicians and pharmacologist who prescribe and dose medications. Differentiating pharmacologic agents who have high versus low volume of distributions is essential in appropriately dosing medications for patients. While physicians generally dose medications in low complexity cases, patients in the intensive care unit might need their medications dosed by a pharmacist. Understanding and calculating different models of distribution, the factors that can affect the volume of distribution, loading dose, and maintenance doses can mean the difference between life and death. When dosing medication, it is of the utmost importance to promptly consult an interprofessional group of specialists.


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Volume of Distribution - Questions

Take a quiz of the questions on this article.

Take Quiz
A drug is administered at a dose of 400 mg intravenously. Its plasma concentration at time zero is 100 mg/L. What is its volume of distribution?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A pharmacologist is studying the pharmacokinetics of an experimental benzodiazepine-type medication in geriatric populations. Data from patients in 2 cohorts with comparable body mass indices (BMI) and glomerular filtration rates (GFR) are analyzed. Cohort A is composed of patients between the ages of 30-45. Cohort B is composed of patients between the ages of 60-75 years old. Each patient was administered a single dose of the drug, and the serum concentration of the drug was measured over time. The experiment concludes that half-life of the drug in cohort B is twice as long as that of cohort A. Assuming that the 100% of the drug is cleared by the kidneys, what is the most likely explanation for these findings?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Following intravenous injection, what is true of any substance which appears to be distributed through 20% to 30% of the body water volume?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following must be determined first when calculating a loading dose?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 48-year-old female with recently diagnosed stage IV breast cancer is enrolled in a clinical trial to study the effects of an experimental immunomodulatory chemotherapeutic agent. Previous pharmacokinetic studies have shown that the drug exhibits a two-compartment model of distribution with a volume of distribution at steady state (Vss) = 10 L/kg and clearance rate (CL) = 12 mL/min/kg. Previous studies also suggested that a plasma concentration of 2.0 mg/L was associated with optimal anti-tumor effects and minimal side effects. Assuming the patient weighs 35 kgs, how much drug should this patient be administered?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which one of the following statements is true regarding a drug's Vd (volume of distribution)?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A previously healthy 4-year old male is brought to the emergency department by his mother who states that the patient has had a 2-day history of progressive total body swelling. The patient also has associated nausea, vomiting, abdominal pain, and excessively foamy urine. The patient was diagnosed with a viral upper respiratory tract infection three days before the onset of his current symptoms. On exam, the patient has periorbital edema, ascites, and pitting edema in bilateral lower extremities. The ED provider decides to give the patient albumin. Given the patient's current presentation, how would the apparent volume of distribution (Vd) of prednisone vary in this patient when given with vs. without albumin?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 68-year-old man with a history of chronic gastroesophageal reflux disease presents to the emergency department with what he reports to be “horrible heartburn.” The patient states that he was walking his dog this morning and began to have severe shortness of breath, nausea, and crushing retrosternal chest pain, which has persisted during rest. The patient also states that he has had similar episodes in the past, which have responded well to effervescent antacids, but they had no effect today. The patient appears diaphoretic in significant distress. A 12-lead ECG reveals ST-segment elevation in leads V1-V3 and reciprocal ST-segment depression in leads II, III & aVF. The patient becomes unconscious and it is decided to administer an 800 mg dose of aspirin rectally. What is the desired plasma concentration of aspirin in this scenario? (Assume Vd of aspirin = 11.9 L, Cl = 3.6 L/hr, t1/2 = 2 hr, oral Bioavailability = 100%, rectal Bioavailability = 40%)



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 42-year-old male with a history of well-controlled hypertension and diabetes mellitus is being prepared for extubation following an elective laparoscopic cholecystectomy. The patient’s pre-operative vitals showed a pulse of 97/min, blood pressure 132/87 mmHg, respiratory rate 16/min, SpO2 97%, and BMI 38. His pre-operative labs were within normal limits. Anesthesia was induced with propofol and lidocaine and maintained with sevoflurane. The patient was also administered rocuronium as a paralytic throughout the operation dosed by total body weight. The anesthetist administers 4 electrical shocks to the ulnar nerve and notices that each muscle contraction is progressively weaker. The patient continues to exhibit these findings, causing a significant delay in extubation but is given a reversal agent which causes the patient to immediately begin breathing spontaneously. What is the most likely cause of the delay in extubating this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Volume of Distribution - References

References

Oie S, Drug distribution and binding. Journal of clinical pharmacology. 1986 Nov-Dec;     [PubMed]
Smith DA,Beaumont K,Maurer TS,Di L, Volume of Distribution in Drug Design. Journal of medicinal chemistry. 2015 Aug 13;     [PubMed]
Toutain PL,Bousquet-Mélou A, Volumes of distribution. Journal of veterinary pharmacology and therapeutics. 2004 Dec;     [PubMed]
Fan J,de Lannoy IA, Pharmacokinetics. Biochemical pharmacology. 2014 Jan 1;     [PubMed]
Faed EM, Protein binding of drugs in plasma, interstitial fluid and tissues: effect on pharmacokinetics. European journal of clinical pharmacology. 1981;     [PubMed]
Mahmood I, Dosing in children: a critical review of the pharmacokinetic allometric scaling and modelling approaches in paediatric drug development and clinical settings. Clinical pharmacokinetics. 2014 Apr;     [PubMed]
Casati A,Putzu M, Anesthesia in the obese patient: pharmacokinetic considerations. Journal of clinical anesthesia. 2005 Mar;     [PubMed]
Zuckerman M,Greller HA,Babu KM, A Review of the Toxicologic Implications of Obesity. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2015 Sep;     [PubMed]
Czock D,Keller F,Rasche FM,Häussler U, Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clinical pharmacokinetics. 2005;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of PA-Hospital Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for PA-Hospital Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in PA-Hospital Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of PA-Hospital Medicine. When it is time for the PA-Hospital Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study PA-Hospital Medicine.