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DRUG DISTRIBUTION

Pharmacokinetic Modeling

approaches

There are three approaches that have been suggested for

pharmacokinetic modeling,

Compartmental model

Physiological model

Model independent approach

Compartmental model

simple compartmental model.

These compartments have no strict physiological or

anatomic basis.

The compartment can represent a body volume, or just

as easily it could represent a chemical state, for example a

metabolite of the drug.

Usually this approach uses one or two compartments.

Despite its simplistic nature, many useful quantities can

be derived using this approach and by comparing

predicted values with actual data.

Physiological model

actual body spaces.

The model is a great deal more complex than the

compartmental models.

Actual transfer and flow rates are employed together with

experimentally measured blood/tissue concentration

ratios.

This model can be used for predictions, and is more

adaptable to clinical therapy and to changing situations

such as alterations of flow rates due to conditions such as

swelling, or fever.

Model independent approach

The is the most recent, and is purely mathematical.

It avoids recourse to kinetic parameters which may not

be valid, and is a lot less complex.

It is good for absorption and elimination rates, and

clearances, but gives no specific information about how

the drug is distributed.

Compartmental model

The compartment concept is utilized in pharmacokinetics

when it is necessary to describe the plasma concentration

versus time data adequately and accurately

To obtain accurate estimates of selected fundamental

pharmacokinetics parameters such as the apparent volume

of drug distribution, the elimination half life and the

elimination rate constant of a drug.

Constitute the basis for the calculation of the dosage

regimen (dose and dosing interval) that will provide the

desired plasma concentration and duration of action for an

administered drug

Compartmental model

Compartmental analysis is the traditional and most

commonly used approach to pharmacokinetic

characterization of a drug.

compartments that communicate reversibly with each

other.

(each organ, tissue or body fluid can a form a

compartment), tissues having approximately similar drug

distribution are pooled to form a kinetically

homogeneous hypothetical compartment.

The selection of a compartment model solely depends upon the distribution

characteristics of a drug following its administration

The equation required to characterize the plasma concentration versus time

data, however, depends upon the compartment model chosen and the route

of drug administration.

The selected model should be such that it will permit accurate predictions in

clinical situations.

Generally, the slower the drug distribution in the body, regardless of the

route of administration, the greater the number of compartments required

to characterize the plasma concentration versus time data, the more complex

is the nature of the equatio

Slow distribution suggests that the distribution equilibrium is attained slowly

and at a finite time (from several minutes to a few hours, depending upon the

nature of the administered drug).

Furthermore, it suggests that the vasculature,tissues and organs are not

behaving in a similar fashion toward this drug and, therefore, it may be

considered that the body to comprise two compartments or, if necessary,

more than two compartments.

Highly perfused systems: liver, the kidney and the blood, may

be pooled together in one compartment (i.e. the central

compartment: compartment 1)

Systems that are not highly perfused; bones, cartilage, fatty

tissue and many others, can also be pooled together and

placed in another compartment (i.e. the tissue or peripheral

compartment: compartment 2).

In this type of model, the rates of drug transfer from

compartment 1 to compartment 2 and back to compartment

1 will become equal at a time greater than zero (from several

minutes to a few hours).

Such compartments are, thus, only mathematical entities

and have no physiological or anatomical meaning.

three compartments arranged parallel to each other are

used to describe kinetics of most drugs.

there is no restriction to the movement of drugs between

compartments as drugs freely move from one

compartment to the other.

It is also assumed that the rate of drug transfer between

compartments and the rate of drug elimination from

compartments follow first-order or linear kinetics.

understood by giving it as intravenous bolus and observing

the manner in which the plasma concentration declines

with time

plasma level-time profile determines the number of

compartments in which a drug will distribute.

Rate of Transfer of drug between

compartments

Rates of reaction

The transfer of drug between the compartments is

represented by rate constants

The rate of a reaction or process is defined as the velocity

at which it proceeds and can be described as either zero-

order or first-order.

Zero-order reaction

Consider the rate of elimination of drug A from the body. If

the amount of the drug, A, is decreasing at a constant rate,

then the rate of elimination of A can be described as:

The reaction proceeds at a constant rate and is

independent of the concentration of A present in the

body.

An example is the elimination of alcohol.

accumulation of plasma levels of the drug and hence

nonlinear pharmacokinetics.

First-order reaction

If the amount of drug A is decreasing at a rate

that is proportional to A, the amount of drug A

remaining in the body, then the rate of

elimination of drug A can be described as:

The reaction proceeds at a rate that is dependent on

the concentration of A present in the body.

first-order reactions and most drugs are eliminated in

this manner.

dosages will show first-order rate processes.

phenytoin and high-dose salicylates.

For drugs that show a first-order elimination process,

as the amount of drug administered increases, the

body is able to eliminate the drug accordingly and

accumulation will not occur.

concentration.

drug administered then all drugs will change from

showing a first-order process to a zero-order process,

for example in an overdose situation.

It is important to note that this does not imply that the

drug concentration in plasma (Cp) is equal to the drug

concentration in the tissues.

quantitatively reflect changes in the tissues.

linear relation; this represents a one-compartment

model.

Conc. vs. time plots

Types of Kinetics Commonly Seen

First Order Kinetics

Zero Order Kinetics

Rate = k C

C = Co e-kt

Rate = k

Rate of elimination

C = Co - kt proportional to

Constant rate of plasma

elimination regardless concentration.

of [D]plasma Constant fraction of

drug eliminated per

C vs. t graph is LINEAR unit time.

C vs. t graph is NOT

linear, decaying

exponential. Log C vs.

t graph is linear.

First-Order Kinetics

Comparison

[drug] decreases linearly [drug] decreases

with time exponentially w/ time

Rate of elimination is Rate of elimination is

constant proportional to [drug]

Rate of elimination is Plot of log [drug] or

independent of [drug] ln[drug] vs. time are

No true t 1/2 linear

t 1/2 is constant regardless

of [drug]

One-Compartment Open Model

One-compartment open model is the simplest model,

which considers the whole body as a single, kinetically

homogeneous unit.

the drug in plasma and other body fluids is attained rapidly

and maintained at all times.

proportional changes in tissue drug concentrations.

The one-compartment open model applies to only those

drugs, which distribute rapidly throughout the body.

following administration of a single dose of a drug, and can

be observed following either intravenous bolus or

extravascular administration of drugs.

Intravenous bolus administration: When a drug that

distributes instantaneously in body is given as rapid IV

bolus, the entire dose of drug enters the body and is

distributed immediately via circulation to all tissues.

In such a situation, the drug concentration-time curve will

be obtained as a straight line on semi-logarithmic paper

showing monophasic exponential decline.

In this model, the decline in plasma drug concentration

occurs only due to elimination of drug from the body,

therefore, the phase is called the elimination phase.

The distribution phase is normally neglected in

calculations because distribution is so rapid that it cannot

be shown on graph.

The extrapolated zero-time intercept of linear elimination

phase gives the coefficient B, and the elimination rate

constant is given by .

of drug in plasma (C0or Cp).

administered by extravascular route (e.g., oral, IM, SC,

etc.), absorption is a pre-requisite for its action.

If it is distributed according to one compartment open

model, the rate of change in drug concentration in the

central compartment is described by 2 exponents - an

absorption exponent and an elimination exponent.

Intravenous bolus administration, one-compartment model

Intravenous bolus administration, one-compartment model

line, which clearly indicates the

presence of a single

pharmacokinetic phase (namely,

the elimination phase.)

Since the drug is administered

intravenously, there is no

absorption phase.

The straight line also suggests

that distribution is instantaneous;

thus the drug is rapidly

distributed in the body.

These data can be accurately and

adequately described by

employing the following mono-

exponential equation

This approach models the entire body as a single

compartment into which drug is added by a rapid single

dose, or bolus.

It is assumed that the drug concentration is uniform in

the body compartment at all times and is eliminated by a

first order process that is described by a first order rate

constant kel.

The one compartment model fails to describe the actual

drug disposition

for example, a particular organ has a small, but strong

affinity for a drug, which does not affect the overall

plasma concentration, but which leads to toxicity on

repeated doses.

If this area is the site of drug action, the effect could

continue after blood levels had subsided.

Extravascular administration: one-compartment model

Two phases in the profile: absorption

and elimination.

The profile clearly indicates the

presence of only one phase in the

post-absorption period.

Since distribution is the sole property

that determines the chosen

compartment model and, since the

profile contains only one phase in the

post-absorption period,

These data can be described accurately

and adequately by employing a one-

compartment model.

However, a biexponential equation

would be needed to characterize the

concentration versus time data

accurately.

Two-Compartment Open Model

Two-compartment open model assumes that body is

composed of two compartments

Central compartment

Peripheral compartment.

blood and highly perfused organs like liver, kidneys, lungs,

heart, brain, etc;

cartilage, etc. make the peripheral compartment

(compartment 2).

The drug is directly administered (IV route) or absorbed

(extravascular route) into the central compartment and

various organs in it rapidly equilibrate with it.

since main organs involved in drug elimination (e.g. liver

and kidneys) are located in it.

through blood (central compartment) and occurs slowly.

It is assumed that drug transfer from central compartment

to peripheral compartment, and back from peripheral

compartment to central compartment occurs by first-order

process and is defined by rate constants denoted by letter

k.

e.g., k12 refers to drug movement from compartment 1

(central compartment) to compartment 2 (peripheral

compartment), and reverse for k21 (Figure 5.2).

the disposition kinetics of most therapeutic agents in

humans and animals.

Intravenous bolus administration:

After the intravenous bolus administration of a drug that

follows two-compartment kinetics, the decline in plasma

concentration is biexponential.

a semi-logarithmic paper, the plasma concentration

declines rapidly in first phase followed by a slow terminal

decline.

attributed mainly to distribution of drug from the central

compartment to the peripheral compartment, and

terminal shallow decline is mainly due to elimination of

drug from the central compartment.

The linear terminal portion of curve is called the

elimination phase.

phase (residual line) is denoted by letter A, and the

elimination phase by letter B

The sum of A and B coefficients gives the initial

concentration of drug in the plasma (C0 or Cp).

distribution, and is the rate constant for elimination; they

are expressed in units of reciprocal time (min1).

body, whereas Kel is used for rate constant for elimination

of drug from the central compartment.

rate constants ( and ) are calculated from the

experimental data by least square regression analysis.

Two-Compartment Open Model, Intravenous administration

Two-Compartment Open Model, Intravenous administration

represents drug distribution in the

body; and only after a finite time

(indicated by a discontinuous

perpendicular line) do we see a straight

line.

The time at which the concentration

versus time plot begins to become a

straight line represents the occurrence

of distribution equilibrium.

This suggests that drug is being

distributed slowly and requires a two-

compartment model for accurate

characterization.

The equation employed to characterize

these plasma concentration versus time

data will be biexponential (contain two

exponential terms):

A and alpha are parameters associated with drug distribution and B and beta are

parameters associated with drug post-distribution phase.

Two compartment model: Extravascular administration:

For a drug that enters the body by an extravascular route

(e.g., oral, IM, SC, etc.) and is distributed according to

two compartment model, the rate of change in drug

concentration in plasma is described by 3 exponents

1. Ka an absorption exponent,

2. a distribution exponent and

3. an elimination exponent.

Extravascular route of drug administration, two-compartment mod

plasma concentration versus time

data for a drug administered by an

extravascular route.

Three phases include absorption,

distribution and post-distribution

The plasma concentration versus time

profile, in the post-absorption period

looks identical to that for an

intravenous bolus two-compartment

model

These data, therefore, can be

described accurately by employing

a two-compartment model and the

equation will contain three

exponential terms (one for each

phase: absorption, distribution, and

postdistribution.)

.

Three-Compartment Open Model

a high affinity for a particular tissue or undergo

redistribution, is best interpreted according to a three

compartment open model.

consisting of three compartments one central and two

peripheral compartments.

The central compartment (Compartment 1) comprises of plasma

and highly perfused organs,

Compartments 2 comprise of moderately perfused tissues e.g.,

skin and muscles

Compartments 3 comprise poorly perfused tissues - e.g., bone,

teeth, ligaments, hair, and fat

it is first distributed immediately into the highly perfused tissues

(compartment 1), then slowly into the moderately perfused

tissues (compartment 2) and thereafter very slowly to the poorly

perfused tissues (compartment 3).

it gives a triexponential appearance.

(a) Plasma concentration versus time profile of a drug showing multicompartment

model. (b) Time profile of a multicompartment model showing

log Cp versus time.

II.NON-COMPARTMENT MODELS/NON-

COMPARTMENT ANALYSIS

time course of drugs in body.

It does not require the assumption of specific compartment

model.

It considers the time course of drug concentration in plasma

as a statistical distribution curve and derives

pharmacokinetic parameters by simple algebraic

equations.

The disadvantage of this method is that it often deals with

averages and provides limited information regarding plasma

drug concentration-time profile.

II.NON-COMPARTMENT MODELS/NON- COMPARTMENT ANALYSIS

The noncompartmental approach for data analysis does not require any specific

compartmental model for the system (body) and can be applied to virtually any

pharmacokinetic data.

Various noncompartmental approaches: statistical moment analysis, system analysis,

or the noncompartmental recirculatory model.

The main purpose of the noncompartmental approach is to estimate various

pharmacokinetic parameters, such as systemic clearance, volume of distribution at

steady state, mean residence time, and bioavailability without assuming or

understanding any structural or mechanistic properties of the pharmacokinetic

behavior of a drug in the body.

In addition, many noncompartmental methods allow the estimation of those

pharmacokinetic parameters from drug concentration profiles without the complicated,

and often subjective, nonlinear regression processes required for the compartmental

models.

Owing to this versatility and ruggedness, the noncompartmental approach is a primary

pharmacokinetic data analysis method for the pharmaceutical industry

Moment analysis, the most commonly used noncompartmental method,

III. PHYSIOLOGICAL MODELS

Physiological models (perfusion rate-limited models)

technique is a newer approach devised to study the time

course of drugs in body.

plus any specialised target site, represents a physiological

compartment.

volume, uptake process, affinity for the compound (i.e.,

partition coefficient) and elimination process.

Thus, the kinetics of the drug is described by a series of flow-

related equations, which can be solved following the

incorporation of known physiological values (e.g., organ or

tissue volume, and perfusion rate) and experimental

estimates (e.g. tissue to plasma partition coefficients)

drawn on the basis of known anatomical and physiological

data and they present a more realistic picture of drug

disposition in various organs and tissues.

impact of altered physiology (e.g. ageing) or pathology on the

drug disposition.

More importantly, species differences can be predicted

based on known perfusion rates.

obtaining experimental data, which is very exhaustive.

A physiological model.

Possibly the simplest application of multi-compartment

model is in the single-cell concentration monitoring (see

the figure above).

If the volume of a cell is V, the mass of solute is q, the

input is u(t) and the secretion of the solution is

proportional to the density of it within the cell, then the

concentration of the solution C within the cell over time

is given by

As the number of compartments increases, the model

can be very complex and the solutions usually beyond

ordinary calculation. Below shows a three-cell model

with interlinks among each other.

The formula for n-cell multi-compartment models

become:

Model topologies

As the number of compartments increase, it is challenging

both to find the algebraic and numerical solutions of the

model.

exist in nature, when the topologies exhibit certain

regularities that the solutions become easier to find.

interconnection of cells and input/output characteristics:

Closed model: No sinks or source, lit.

Open model: There are sinks or/and sources among cells.

Catenary model: All compartments are arranged in a

chain, with each pool connecting only to its neighbors.

This model has two or more cells.

Cyclic model: It's a special case of the catenary model,

with three or more cells, in which the first and last cell are

connected

Mammillary model: Consists of a central compartment

with peripheral compartments connecting to it. There are

no interconnections among other compartments.

Reducible model: It's a set of unconnected models.

Pharmacokinetic parameters

Elimination rate constant

Consider a single IV bolus injection of drug X.

As time proceeds, the amount of drug in the body is

eliminated.

Thus the rate of elimination can be described (assuming

first-order elimination) as:

Hence

X= X0 exp(kt)

where X amount of drug X, X0 dose and k first-order

elimination rate constant.

Volume of distribution

The volume of distribution (Vd) has no direct

physiological meaning; it is not a real volume and is

usually referred to as the apparent volume of

distribution.

It is defined as that volume of plasma in which the

total amount of drug in the body would be required to

be dissolved in order to reflect the drug concentration

attained in plasma.

drug (Cp) in plasma is not necessarily the same in the

liver, kidneys or other tissues.

Then

Cp (plasma) =Vd X (tissues)

where Vd is the constant of proportionality and is

referred to as the volume of distribution, which thus

relates the total amount of drug in the body at any

time to the corresponding plasma concentration. Thus

Half-life

The time required to reduce the plasma

concentration to one half its initial value is

defined as the half-life (t1/2).

Consider

ln Cpt = ln Cp0 kt

Let Cp0 decay to Cp0/2 and solve for t=t1/2

This parameter is very useful for estimating how long

it will take for levels to be reduced by half the

original concentration.

be stopped if a patient has toxic drug levels, assuming

the drug shows linear one-compartment

pharmacokinetics.

Clearance

Drug clearance (CL) is defined as the volume of

plasma in the vascular compartment cleared of drug

per unit time by the processes of metabolism and

excretion.

Clearance for a drug is constant if the drug is

eliminated by first-order kinetics.

Drug can be cleared by renal excretion or by

metabolism or both. With respect to the kidney and

liver, etc., clearances are additive, that is:

CLtotal =CLrenal + CLnonrenal

Mathematically, clearance is the product of the first-

order elimination rate constant (k) and the apparent

volume of distribution (Vd).

i.e. the fractional rate of drug loss from the volume

of distribution.

Clearance is related to half-life by

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