Chapter 2: Multicompartment Model
Introduction
Pharmacokinetic models are simplifications of complex biological processes. The
multicompartment model is an extension of the one-compartment model and is used when
drug distribution and elimination do not follow a simple mono-exponential pattern. This
model considers the body as a system composed of multiple compartments based on
distribution characteristics, perfusion, and drug affinity. Most commonly, two- and three-
compartment models are used in pharmacokinetics.
Each compartment is assumed to be kinetically homogeneous, meaning the drug
concentration within a compartment is uniformly distributed at any given time. However,
the drug may distribute at different rates between compartments, allowing
multicompartment models to more accurately describe the pharmacokinetics of many drugs
compared to simpler models.
These models are especially useful when the plasma concentration-time curve
demonstrates a biphasic or multiphasic pattern, which reflects rapid distribution followed
by a slower elimination phase.
Objectives of Multicompartment Models
• Define the pharmacokinetics of two- and three-compartment models.
• Understand distribution and elimination phases.
• Define and calculate parameters: α, β, t½, Vp, VD (ss), Cl, and AUC.
• Understand the assumptions of the models.
• Estimate parameters using the method of residuals.
• Differentiate between central and peripheral compartments.
2.1 Two-Compartment Model
In the two-compartment model, the body is represented by a central compartment (blood,
plasma, and highly perfused tissues) and a peripheral compartment (less perfused tissues
such as muscles).
Drugs administered via IV bolus first distribute rapidly in the central compartment and then
slowly diffuse into the peripheral compartment. The decline in plasma concentration
follows a biphasic pattern: an initial rapid distribution phase (α-phase) and a slower
elimination phase (β-phase).
Assumptions of the Two-Compartment Model
• Drug distributes instantaneously in the central compartment.
• Transfer between compartments follows first-order kinetics.
• Elimination occurs only from the central compartment. (Drug elimination is presumed
to occur from the central compartment, because the major sites of drug elimination
(renal excretion and hepatic drug metabolism) occur in organs, such as the kidney and
liver, which are highly perfused with blood.)
• Drug distribution and elimination occur simultaneously during the distribution phase.
2.2 Comparison Between One-Compartment and Multi-Compartment Models.
One-Compartment Multi-Compartment
The body is considered as a single kinetically The body consists of more than one
homogenous unit that has no barrier to drug compartment, consisting of central compartment
movement. (highly perfused organs) and peripheral
compartment (tissues).
It is assumed that the administered drug is It explains the observation that drug does not
distributed/equilibrated instantaneously and equilibrate/distribute instantaneously and
rapidly throughout the body. rapidly throughout the body due to different
drug affinity to different tissues.
Plasma-level time curve declines linearly Plasma-level time curve follows different rates
for different tissues.
To define such compartment, you need To define such compartment, you need to
describe VD, CLT and k Parameters. calculate α, and β, t½, Vi, VdSS, Cl and AUC
parameters.
2.3 Phases of Plasma Level–Time Curve
• Distribution Phase (α): This phase represents the initial, rapid decline in plasma drug
concentration immediately after an intravenous (IV) bolus injection. The decline is
primarily due to the redistribution of the drug from the central compartment (which
includes the blood and highly perfused organs such as the heart, liver, and kidneys) to
the peripheral compartment (which includes less perfused tissues such as fat and
muscle). During this phase, drug elimination (e.g., via liver metabolism or renal
excretion) is minimal, and the observed concentration drop is largely a result of drug
distribution throughout the body.
• Elimination Phase (β): After the distribution phase is complete, the drug reaches a
pseudo-equilibrium between the central and peripheral compartments. From this point
onward, the decline in plasma drug concentration becomes slower and primarily
reflects the rate of drug elimination from the body. In this phase, drug removal
mechanisms such as hepatic metabolism and renal excretion dominate, while
distribution processes have already stabilized. The elimination phase usually
determines the terminal half-life of the drug.
Relationship between tissue and plasma drug concentrations of a two-compartment
model
How the Drug Moves
1. After IV injection, the drug first goes into the plasma (central compartment).
2. From there, it distributes to the tissue (peripheral compartment).
3. With time, the drug can move back from tissue to plasma.
4. Eventually, the body eliminates the drug from the plasma (central compartment).
o Immediately after an IV bolus dose, the drug enters the central compartment (plasma),
so the plasma concentration is high, but the tissue concentration is still low because the
drug has not yet had time to distribute.
o Over time, the drug begins to move from the plasma to the tissue compartment. As a
result, the plasma concentration decreases and tissue concentration increases. This
process is known as the distribution phase. During this phase, the concentrations in the
two compartments are not in equilibrium—the drug is still moving into the tissues.
o After a certain time, a distribution equilibrium is reached, meaning that the rate of drug
entering the tissue equals the rate leaving the tissue. At this point:
• Distribution is complete and the body is now primarily focused on eliminating the
drug.
• The ratio of tissue to plasma concentration becomes constant, even though the
actual amounts are decreasing due to elimination.
• This is called the post-distribution or elimination phase, where both compartments
decline in concentration in parallel.
• Although the drug continues to be eliminated from the body (usually through
metabolism or excretion), this elimination mainly happens from the central
compartment (plasma).
• Because the tissue and plasma are now in equilibrium, the drug leaving the plasma
is quickly replaced by drug moving from the tissue back into plasma — and vice
versa — maintaining a constant ratio between tissue and plasma concentrations.
• What this means is even though the total amount of drug in the body is decreasing,
the proportional relationship between plasma and tissue drug concentrations
remains steady. In other words, they decline at the same rate, in parallel.
Rate Constants/Transfer Constants/Micro-constants
The rate constants for the transfer of drug between compartments are referred to as
microconstants or transfer constants. They relate the amount of drug being transferred per
unity time from one compartment to other.
The movement of drug is characterized by first-order rate constants:
- k12: from central to peripheral compartment
- k21: from peripheral back to central compartment
- k10: elimination from central compartment
Elimination primarily occurs in organs like the liver and kidney, which are part of the
central compartment.
2.4 Pharmacokinetic Parameters in Two-Compartment Model
In the two-compartment model, drug concentration in plasma after an IV bolus injection is
described by a biexponential equation:
Cp = Ae-αt + Be-βt
Where:
• Cp = Plasma concentration at time t
• A and B = y-intercepts of distribution and elimination phases respectively
• α = Rate constant for distribution phase (rapid)
• β = Rate constant for elimination phase (slower)
Key Parameters
• t½α = 0.693 / α → Half-life of the distribution phase
• t½β = 0.693 / β → Half-life of the elimination phase
• Vp = Volume of central compartment
• Vd = Apparent volume of distribution (several types: Vdβ, VdSS, Vexp)
• Cl = Total body clearance = k × Vd
• AUC = Area Under the Curve: AUC = A/α + B/β
2.5 Method of Residuals
This method is used to separate the distribution and elimination phases from plasma drug
concentration–time data when a two-compartment model is suspected.
Steps:
• Plot Cp versus time on semi-log graph paper
• Identify the terminal phase (β-phase) and extrapolate it back to estimate B and β
• Subtract extrapolated points from original data to get residuals (Cp - Cp′)
• Plot log residuals against time to determine the α-phase
• Calculate slope and y-intercept of α-line to get α and A
2.6 Conceptual Understanding: Significance of Volumes of Distribution
The equation:
(VD)exp > (VD)β > Vp
represents the different apparent volumes of distribution used in pharmacokinetics to
describe how a drug distributes within the body. The hierarchy of these volumes is based
on how extensively the drug moves from the central compartment (plasma) into peripheral
tissues over time.
Imagine administering an intravenous (IV) drug into a patient’s bloodstream. The drug
follows different distribution phases:
Vp (Plasma Volume / Central Compartment Volume):
o This is the smallest volume and represents the drug's initial distribution in the
central compartment, mainly the blood plasma and highly perfused organs
(like the heart, liver, and kidneys).
o It reflects the volume in which the drug would be distributed if it stayed only
in plasma and didn’t move to deeper tissues.
o Example: Heparin, which largely remains in the bloodstream.
(VD)β (Volume of Distribution in the Elimination Phase / Terminal Phase VD):
o As time progresses, the drug distributes into tissues, and equilibrium between
plasma and tissue is achieved.
o This volume accounts for the drug’s presence in both plasma and peripheral
compartments, such as muscle, and organs with moderate blood flow.
o It is larger than Vp because it includes additional drug distribution into deeper
compartments.
o Example: Theophylline, which distributes moderately into tissues beyond plasma.
(VD)exp (Extrapolated Volume of Distribution):
o This is the largest theoretical volume because it is estimated based on extrapolation
of the drug’s elimination kinetics. It’s usually the largest because it accounts for
everything.
o It assumes that the drug has been distributed to all possible tissues and
compartments, including those that slowly accumulate the drug over time (e.g.,
fat tissue, deep compartments).
o It often overestimates the real distribution volume due to assumptions made during
pharmacokinetic modeling.
o Example: Digoxin, which extensively binds to tissues like cardiac muscle and
skeletal muscle, leading to a very high Vd.
Physiological Interpretation:
• Vp is the smallest distribution volume and represents the drug confined to plasma
and highly perfused organs such as the heart, liver, and kidneys. It is the lowest
because it does not consider drug penetration into less perfused tissues.
• (VD)β reflects the drug distribution in moderately perfused tissues such as muscle,
and skin. It is larger than Vp because it includes both plasma and these additional
compartments.
• (VD)exp is the largest theoretical volume because it assumes that the drug is
distributed across all possible compartments, even minor ones. It represents an
overestimated value of distribution.
Key Takeaways in Drug Distribution:
• Drugs with small VD (close to Vp) tend to remain in plasma, often due to high
plasma protein binding (e.g., warfarin).
• Drugs with moderate VD (closer to (VD)β distribute into tissues but not extensively
(e.g., aminoglycosides).
• Drugs with very high VD (approaching (VD)exp accumulate in deep tissues, often
due to lipophilicity and tissue binding (e.g., chloroquine, digoxin).
2.7 Significance of (VD)β in CHF (Congestive Heart Failure) Patients
𝐷0
(VD)β =
𝛽[𝐴𝑈𝐶]∞
0
In a study involving a cardiotonic drug, which was given intravenously to a group of normal
and CHF patients, the average AUC for CHF was 40% higher than in the normal subjects.
The elimination constant (β) was 40% less in CHF patients, whereas the average (VD)β
remained the same. The reason of this VD remaining constant is due to the 40% increase in
AUC in the CHF subjects being offset by a 40% smaller β estimated by using computer
methods. Because the dose was the same, the (VD)β would not change unless the increase
in AUC is not accompanied by a change in b elimination constant.
2.8 Is VDSS a function of transfer constant (k12 and k21)?
At steady state conditions,
Rate of drug entry into tissue compartment from central compartment = rate of drug exit
from tissue compartment to central compartment.
Rates of drug transfer is described by Dt k21 = Dp k12 --------- (1)
Here, Dt = amount of drug in tissue compartment
Dp = amount of drug in central compartment
k12 = rate constant for drug moving from central to tissue compartment
k21 = rate constant for drug moving from tissue to central compartment
𝑫𝒑 𝒌𝟏𝟐
Rearranging equation (1), 𝑫𝒕 = ---------(2)
𝒌𝟐𝟏
We know, Dp = CpVp -------- (3);
If we put the value of Dp in the equation (2),
𝑪𝒑 𝑽𝒑 𝒌𝟏𝟐
𝑫𝒕 = --------------(4)
𝒌𝟐𝟏
Again,
Total amount of drug in the body at steady state (ss) = Amount of drug in tissue
compartment + Amount of drug in central compartment = Dt + DP
Thus,
𝑇𝑜𝑡𝑎𝑙 𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑏𝑜𝑑𝑦
Apparent VD at Steady-State =
𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑐𝑒𝑛𝑡𝑟𝑎𝑙 𝑐𝑜𝑚𝑝𝑎𝑟𝑡𝑚𝑒𝑛𝑡
𝑫𝒕 +𝑫𝒑
VDss = --------- (5)
𝑪𝒑
Putting value of Dp from equation (3) and Dt from equation (4) in equation (5), we will get,
𝑪𝒑𝑽𝒑 𝒌𝟏𝟐
𝒌𝟐𝟏
+ 𝑪𝒑 𝑽𝒑
VDss =
𝑪𝒑
𝑽𝒑𝒌𝟏𝟐
𝑪𝒑 (
𝒌𝟐𝟏
+ 𝑽𝒑 )
=
𝑪𝒑
𝒌𝟏𝟐 𝑽𝒑
= + 𝑽𝒑
𝒌𝟐𝟏
𝑘12 𝑉𝑝
Thus, VDss = + 𝑉𝑝
𝑘21
This proves that Apparent Volume of Distribution at Steady-State is the function of
transfer constants.
2.9 Drug Clearance and Elimination Rate Constant
Drug Clearance
𝑫𝟎
𝑪𝒍 = ------ (1)
[𝑨𝑼𝑪]∞𝟎
Cl = (VD)β ------------ (2)
Clearance is the volume of plasma that is cleared of drug per unit time. In (1) Equation, to
determine the [AUC]0∞, we need to take frequent samples to get early time point
concentrations and its rapid decline for drugs with multicompartment pharmacokinetics.
The equation (2) can be followed for two-compartment models and can simply be measured
if the parameters are known.
Clearance is a term that is useful in calculating average drug concentrations. With many
drugs, a biphasic profile suggests a rapid tissue distribution phase followed by a slower
elimination phase. Multicompartment pharmacokinetics is an important consideration in
understanding drug permeation and toxicity. For example, the plasma–time profiles of
aminoglycosides, such as gentamicin, are more useful in explaining toxicity than average
plasma or drug concentration taken at peak or trough time.
Elimination Rate Constant
In the two-compartment model (IV administration),
K (elimination rate constant) represents the elimination of drug from the central
compartment,
And β represents drug elimination during the beta or elimination phase, when distribution
is mostly complete.
Because of redistribution of drug out of the tissue compartment, the plasma drug level
curve declines more slowly in the β phase. Hence β is smaller than k; thus, k is a true
elimination constant, whereas β is a hybrid elimination rate constant that is influenced by
the rate of transfer of drug into and out of the tissue compartment. When it is impractical
to determine k, β is calculated from the β slope. The t1/2β is often used to calculate the drug
dose.
2.10 Three-Compartment Model
In a three-compartment model, the drug distributes into:
• Central compartment (plasma and rapidly perfused tissues)
• Peripheral compartment (moderately perfused tissues)
• Deep tissue compartment (poorly perfused tissues like fat and bone)
• Right after a drug is administered, highly perfused organs (like the brain, liver, and
kidneys) receive it quickly because they have rich blood supply.
• In contrast, fat and bone have low blood flow, so the drug enters these tissues very
slowly. This means that early on, fat storage doesn’t affect plasma concentration much.
• The mamillary model is more commonly used because it can better represent the
distribution in the body.
• After a drug is distributed to peripheral tissues, it can redistribute back into the
bloodstream/central compartment, which is a common phenomenon, especially with
lipophilic drugs that accumulate in fat. This redistribution is better represented by the
mamillary model than by simpler models like the catenary model.
The plasma concentration-time profile is triexponential:
Cp = Ae-αt + Be-βt + Ce-γt, where α > β > γ
Key Characteristics
• Complex drug distribution and slower terminal elimination
• Used for drugs with very slow tissue redistribution (e.g., digoxin, fentanyl)
• Each compartment exchanges with central, not directly with each other
2.11 Plasma Profile of Three Compartment Model
1. Alpha Phase (Rapid Distribution Phase)
• Immediately after injection, the drug spreads quickly from the central compartment
(blood plasma) into highly perfused tissues (like the liver, kidneys, and muscles).
• This causes a steep drop in plasma concentration as the drug is moving out of the blood
into tissues.
2. Beta Phase (Elimination Phase)
• Once the rapid distribution stabilizes, the drug is gradually eliminated from the central
compartment.
• The liver metabolizes the drug, and the kidneys excrete it.
• The decline in plasma concentration now follows a less steep slope compared to the
alpha phase.
3. Gamma Phase (Slow Redistribution Phase)
• Some drugs get stored in deep tissues like fat and bone and gradually leak back into the
bloodstream.
• As plasma levels drop (due to elimination), the concentration in fat and bone becomes
higher than in blood, causing the drug to slowly move back into circulation.
• This gradual release leads to a slow decline in plasma concentration, forming a long
tail on the graph.
• By the time the gamma phase is reached, most of the drug has already been
metabolized, and only a small amount remains in circulation. This leaves the slow
tissue leakage as the only remaining source.
• This phase can last days to weeks, especially for fat-soluble drugs, as fat and bone have
poor blood flow, making drug release very slow.
2.12 Clinical Applications and Comparisons
Clinical Applications
• Multi-compartment models help in accurate dosing of drugs with complex kinetics
• Used to predict tissue accumulation, toxicity, and therapeutic outcomes
• Critical for IV administration of potent drugs with narrow therapeutic index
Comparison with One-Compartment Model
• One-compartment: Assumes instant and uniform distribution
• Two-compartment: Accounts for distribution delay to peripheral tissues
• Three-compartment: Adds deep tissue compartment for slowest equilibrating drugs
• One-compartment: Mono-exponential decline, simpler analysis
• Multi-compartment: Bi/tri-exponential decline, complex but more accurate