Chapter 8

Pharmacokinetics
Definition:
Pharmacokinetic is defined as the kinetics of drug absorption, distribution, metabolism and excretion
(ADME) and their relationship with the pharmacologic, therapeutic or toxicologic response in human and
animals.

PHARMACOKINETICS MODELS
A model is a hypothesis using mathematical terms to describe quantitative relationships.
The mathematical model used to calculate absorption, distribution and elimination are known as
pharmacokinetic model. The pharmacokinetic models express the time course of drug throughout the body.
It is also used to predict concentration of drugs in body fluid after administering dose. It is also used to
predict the behaviors of drugs in patients.

Applications of Pharmacokinetic Models 3

Pharmacokinetic models are useful in 4
1. Characterizing the behaviour of drugs in patients.
2. Predicting the concentration of drug in various body fluids with any dosage regimen.
3. Predicting the multiple-dose concentration curves from single dose experiments.
4. Calculating the optimum dosage regimen for individual patients.
5. Evaluating the risk of toxicity with certain dosage regimens.
6. Correlating plasma drug concentration with pharmacological response.
7. Evaluating the bioequivalence/bioinequivalence between different formulations of the same drug.
8. Estimating the possibility of drug and/or metabolite(s) accumulation in the body.
9. Determining the influence of altered physiology/disease state on drug ADME.
10. Explaining drug interactions.
  TYPE OF PHARMACOKINETICS MODELS

They are of three different types

l. Compartment models
2. Physiological models
3. Non- Compartment models

1. Compartment models:
It is assumed that the body consists of series of compartments. Each compartment may exchange material
with other compartments. A compartment is not real physiologic or anatomic region but it is considered as
tissues have same blood flow and affinity for drugs. The compartment is "well stirred" and distribution of
drug is uniform and rapid within each Compartment. The rate of movement of drug within compartmtents
follows first order kinetic. Rate constant are used to express the overall rate process of drugs come in and
out from the Compartment. Compartment models are divided into Mammillary and Caternary Model.

a. Mammillary Model:
This model is the most common compartment model used in pharmacokinetics. The model consists of
central compartment and peripheral compartments. The peripheral Compartments are connected to central
compartment.
 Central Compartment: It comprise of blood and highly perfuse tissues like liver, lungs, kidneys, etc.
that equilibrate with the drug rapidly. Elimination usually occurs from this compartment.
 peripheral compartment: It comprise of poorly perfuse and slow equilibrating tissues such as
muscles, skin, adipose tissues etc. and considered as a hybrid of several functional physiological
units.
2. Caternary Model: It consists of compartments which are joined to one another like compartments of
train. This model is rarely used.

Advantages of compartment model:

 The compartment model provides visual presentation of rate processes involved in drug disposition.
 This model enables to estimate drug concentration time profile in normal and pathological condition.
 It is also helpful in dosage form development of dosage regimen.
 It helps pharmacokineticist to write differential equation for each of the rate process to explain drug
concentration changes in individual compartment.
Disadvantages of compartment model:
 The model may differ within a study population.
 The model is applicable to specific drug under observation.
 The model depends on curve fitting of plasma concentration with multiexponential mathematical
equation.

2. Physiological models
In this model, absorption, distribution and elimination of drug is represented as series of organs or tissue
spaces. The drug concentration profile has drawn from the uptake and elimination capacity of organs
composing the body. The distribution of the drug to an organ based on the blood flow to the organ, the organ
size and the partition coefficient of the drug between blood and the organ. The elimination capacities are
based on the drug and the organ involved. The overall drug concentration profile results from the sum of the
Processing of the drug by different organs. Lungs, liver, brain and kidney are rapidly equilibrating tissue
(RET) and muscles and adipose are considered as slowly equilibrating tissue (SET).
Physiologic models are either blood flow rate limited model or membrane permeation rate limited
model. The blood flow rate limited model are also called perfusion rate limited model. These models are
applicable to low molecular weight, highly lipophilic and poorly ionized drugs such as lidocaine and
thiopental etc. While Membrane permeation rate limited model are also called diffusion limited models.
These models are applicable to highly polar, ionized and charged drugs.
Advantages of Physiological models
 It is more realistic model.
 The mathematical treatment is straight forward.
 NO date fitting is required in this model.
 The model provides better picture of drug concentration time profile in an organ or tissue.
 The extrapolation of animal data in the prediction of human pharmacokinetics is simple by using this
model.
Disadvantages of Physiological models
It is very exhaustive process and monitoring of drug concentration in body is difficult.

3. Non Compartment Analysis

They are also considered as model-independent method because they do not rely upon assumptions about
body compartments. It relies upon algebraic equations to detect Pharmacokinetic parameters and therefore
making the analysis less complex. The blood or plasma samples are collected from study subjects and
analyzed. The noncompartmental approach, based on the statistical moments theory, involves collection of
experimental data following a single dose of drug.
The amount of drug in the body is proportional to the concentration in plasma at all time points. By making
these substitutions, we can calculate MRT
AUMC
MRT 
AUC
MRT = Mean Residence Time
AUMC= Area under first moment curve
AUC= Area under zero moment curve
MRT is defined as the average time spent by drug in the body before elimination.
AUMC is obtained from plot of product of plasma drug concentration and time vs time (t) from zero to
infinity.
AUC is obtained from a plot of plasma drug concentration versus time from zero to infinity.
Practically, the AUMC and AUC can be calculated from the respective graphs by the trapezoidal rule

MRT is defined as the average amount of time spent by the drug in the body before being eliminated. In this
sense, it is the statistical moment analogy of half-life, t½. In effect, MRT represents the time for 63.2% of
the intravenous bolus dose to be eliminated.
The values will always be greater when the drug is administered in a fashion other than i.v. bolus.
Applications of noncompartmental technique includes 3
1. It is widely used to estimate the important pharmacokinetic parameters like bioavailability, clearance and
apparent volume of distribution.
2. The method is also useful in determining half-life, rate of absorption and first order absorption rate
constant of the drug.
Advantages of noncompartmental method include 4
1. The calculations involved simple algebraic equations.
2. The same mathematical expression can be applied to all drugs or metabolites that follow first-order
kinetics.
3. A detailed description of drug disposition characteristics is not required.
Disadvantages of this method include –
1. It provides limited information regarding the plasma drug concentration-time profile. More often, it deals
with averages.
2. The method does not adequately treat non-linear cases.
 ONE COMPARTMENT OPEN MODEL

Question: Explain in detail one compartment model.

 The one-compartment open model is the simplest model which depicts the body as a single, kinetically
homogeneous unit that has no barriers to the movement of drug and final distribution equilibrium
between the drug in plasma and other body fluids is attained instantaneously and maintained at all the
time.
 This model thus applies only to those drugs that distribute rapidly though out the body.
 The concentration of drug in plasma represents the drug concentration in all body tissues.
 The term <open= indicates that the input (availability) and output (elimination) are unidirectional and
that the drug can be eliminated from the body.

ka Blood and Metabolism

Drug kE
Input Other Body
Output
(Absorption) Tissues ( Elimination ) Excretion

Depending upon the rate of input, several one-compartment open models can be defined:
 One-compartment open model, i.v. bolus administration
 One-compartment open model, continuous i.v. infusion
 One-compartment open model, e.v. administration, zero-order absorption
 One-compartment open model, e.v. administration, first-order absorption

 Intravenous bolus administration

 When a drug that distributes rapidly in the body is given in the form of a rapid intravenous injection
(i.e IV bolus dose), it takes about 2 to 3 minutes for complete circulation and therefore the rate of
absorption is neglected in calculations. The model can be depicted as follows:

Blood and kE
Other Body
Tissues

 The general expression for rate of drug presentation to the body is:
dX/dt = Rate in (availability) - Rate out (elimination) .................. (1)
 Since rate in or absorption is absent, the equation becomes:
 dX/dt =  Rate out ....................(2)
 If the rate out or elimination follows first-order kinetics, then:
dX
  K ΕX
dt ……………(3)
 where, KE = first-order elimination rate constant, and
X = amount of drug in the body at any time t remaining to be eliminated.
 Negative sign indicates that the drug is being lost from the body.

Estimation of Pharmacokinetic Parameters

 For a drug that follows one-compartment kinetics and administered as rapid i.v. injection, the decline
in plasma drug concentration is only due to elimination of drug from the body (and not due to
distribution), the phase being called as elimination phase. Elimination phase can be characterized
by 3 parameters4
1. Elimination rate constant
2. Elimination half-life
3. Clearance.
 Elimination Rate Constant: Integration of equation 3 yields:
ln X = ln Xo – KE t ............. (4)
 Where, Xo = amount of drug at time t = zero i.e. the initial amount of drug injected.
 Equation 4 can also be written in the exponential form as:
X = Xo e–KEt ................. (5)
 The above equation shows that disposition of a drug that follows one-compartment kinetics is
monoexponential.
 Transforming equation 4 into common logarithms (log base 10), we get:
K t ………..(6)
log X  log X0 - E
2.303
 Since it is difficult to determine directly the amount of drug in the body X, advantage is taken of the
fact that a constant relationship exists between drug concentration in plasma C (easily measurable)
and X; thus:
X = Vd / C ................ (7)
 where, Vd = proportionality constant popularly known as the apparent volume of distribution. It is a
pharmacokinetic parameter that permits the use of plasma drug concentration in place of amount of
drug in the body. The equation 6 therefore becomes:
K t
log C  log C0 - E ………..(8)
2.303
  where, Co = plasma drug concentration immediately after i.v. injection.
 Equation 8 is that of a straight line and indicates that a semilogarithmic plot of log C versus t will be
linear with Y-intercept log Co. The elimination rate constant is directly obtained from the slope of the
line (Fig. 1). It has units of min31.

Elimination Half-Life (biological half-life):

 It is defined as the time taken for the amount of drug in the body as well as plasma concentration to
decline by one-half or 50% its initial value. It is expressed in hours or minutes. Half-life is related to
elimination rate constant by the following equation:

i.e. at time t=0 C = C0.

C0
C
and at time t = t1/2 2

 Substituting the values of t and C in the logarithmic form of eqn. (iii) yields:
log (C0/2) = log C0  (kE / 2.303) t1/2.
kE C0
t  log
or, 2.303 1/ 2 C0 / 2

log 2x2.303 0.301x2.303 0.693

t1/ 2   
kE kE kE

0.693
t1 / 2  k
E

 Elimination half-life can be readily obtained from the graph of log C versus t.
  Apparent Volume of Distribution:
 Since these parameters are closely related with the physiologic mechanisms in the body, they are
called as primary parameters.
Vd is a measure of the extent of distribution of drug and is expressed in liters.
Amountof drug in thebody X
Vd  
Plasma drug concentration C
 It is determined by administering it by rapid i.v. injection and using the following equation:
X0 i.v. bolus dose
Vd  
C0 plasma concentration at timet  0

 The C0 value is obtained by extrapolation of the plot of log(plasma conc) vs time.

 A more general, more useful non-compartmental method that can be applied to many compartment
models for estimating the Vd. Vd can be determined by another way if the AUC and the first order
elimination rate constant, kE is known.
 For drug given as IV bolus,
Vd = Xo / KE.AUC
 For drug given as extravascularly
Vd = FXo / KE.AUC
 Where Xo = dose administered and F= fraction of drug absorbed into systemic circulation.
 The calculation of Vd by means of the above equation is model independent because no
pharmacokinetic model is considered while calculating and the AUC is determined by the
trapezoidal rule.

 Clearance:
 Clearance is the most important parameter in clinical drug applications and is useful in evaluating the
mechanism by which a drug is eliminated by the whole organism or by a particular organ.
 Clearance is defined as the theoretical volume of body fluid containing drug (i.e. that fraction of
apparent volume of distribution) from which the drug is completely removed in a given period of
time. It is expressed in ml/min or liters/hour.
Rate of e limination [mg / min]
Clearance   [ml / min]
Plasma concentration [mg / ml]

(dX / dt)  k E X  k E Vd C
CL     k EV d
C C C
 The negative sign refers to the drug exiting from the body.
Total Body Clearance: (total systemic clearance) Elimination of a drug from the body involves processes
occurring in kidney, liver, lungs and other eliminating organs. Clearance at an individual organ level is
called as organ clearance. It can be estimated by dividing the rate of elimination by each organ with the
concentration of drug presented to it. Thus,

Renal clearance ClR = Rate of Elimination by kidney/C

Hepatic clearance ClH = Rate of Elimination by liver/C

Other organ clearance Clothers = Rate of elimination by other organs/C

Total Systemic Clearance, CLT = CLR + CLH + CLOthers

Clearance by all organs other than kidney is sometimes known as nonrenal clearance ClNR. It is the
difference between total clearance and renal clearance.
ClT = KE.X/C
Since X/C = Vd equation can be written as
ClT = KEVd
Since KE = 0.693 / t½, clearance can be related to half-life by the following equation:
CLT = 0.693 Vd / t1/2

The non compartmental method of computing total clearance of a drug that follows one compartment kinetic
is:
For drugs given as IV bolus,
CLT = X0/AUC
For drugs administered extravascularly
CLT = FX0/AUC
ORGAN CLEARANCE
Rate of elimination by organ= rate of presentation to the organ 3 rate of exit from the organ.

Rate of elimination = Q. Cin- Q. Cout

(Rate of extraction) =Q (Cin- Cout)

Cl organ = rate of extraction / Cin

= Q (Cin - Cout) / Cin

=Q . Er .................... (eq 1)
Question: Discuss extraction ratio and hepatic clearance in detail.
Extraction ratio:

ER= (Cin - Cout) / Cin

ER is an index of how efficiently the eliminating organs clear the blood flowing through it of drug.
It has no units and its value ranges from zero (no elimination) to one (complete elimination). Based on ER
values, drugs can be classified into 3 groups:
Drugs with high ER (above 0.7)
Drugs with intermediate ER (between 0.7-0.3)
Drugs with low ER (below 0.3)
The fraction of drug that escapes removal by organ is expressed as
F= 1- ER
Where F = systemic availability when the eliminating organ is liver.

Hepatic Clearance: For certain drugs, the nonrenal clearance can be assumed as equal to hepatic clearance
ClH. It is given as:
ClH = ClT – ClR
An equation can also be written for hepatic clearance:
ClH = QH. ERH
where, QH = hepatic blood flow (about 1.5 liters/min), and
ERH = hepatic extraction ratio.
The hepatic clearance of drugs can be divided into two groups:
1. Drugs with hepatic blood flow rate-limited clearance, and
2. Drugs with intrinsic capacity-limited clearance.
1. Hepatic blood flow
 When ERH is one, ClH approaches its maximum value. In such a situation, hepatic clearance is said
to be perfusion rate limited or flow dependent.
 Alteration in hepatic blood flow significantly affects the elimination of drugs with high ERH example
propanol, lidocaine, etc.
 First pass hepatic extraction is suspected when there is lack of unchanged drug in systemic
circulation after oral administration.
 Maximum oral availability F for such drugs can be computed from equation. An extension of the
same equation is the non compartmental method of estimating F:
F= 1- ERH
 2. Intrinsic Capacity Clearance
 It is defined as the inherent ability of an organ to irreversibly remove a drug in the absence of any
flow limitation
 It depends in this case upon the enzyme activity.
 Drugs with low ERH and drugs with elimination primarily by metabolism are greatly affected by
enzyme activity.
 Hepatic clearance of such drugs is said to be capacity limited example theophylline.
 Hepatic clearance of drugs with low ER is independent of blood flow rate but sensitive to changes in
protein binding.





Question: Discuss one compartment open model, I.V. infusion model and discuss the effect of
loading IV injection dose. Describe the derivation of various pharmacokinetic
parameters for the model.

One-Compartment Open Model

 Intravenous Infusion
 Rapid IV injection is unsuitable when the drug has potential to precipitate toxicity or when
maintenance of a stable concentration or amount of drug in the body is desired.
 In such a situation, the drug is administered at a constant rate (zero order) by IV infusion.

Advantages of such a zero order infusion of drugs include-

 Ease of control of rate of infusion to fit individual patient needs.
 Prevents fluctuating plasma level (maxima and minima), desired especially when the drug has a
narrow therapeutic index.
 Other drugs, electrolytes and nutrients can be conveniently administered simultaneously by the same
infusion lie in critically ill patients.

 At any time during infusion, the rate of change in the amount of drug in the body, dX/dt is the
difference between the zero order rate of drug infusion Ro and first order elimination, 3 KEX:
…………..(1)
dX
 R K X
 Integration and rearrangemdetnt of ab0ove eqEuation yields:
R0
X (1 e -K E t ) …………..(2)
KE
 Since X = Vd C, the equation 2 can be transformed into concentration terms as follows:
R0 R0 …………..(3 & 4)
C (1 e -K E t )  (1 e -K E t )
K E Vd ClT
 After infusion, as time passes, amount of drug rises gradually (elimination rate less than the rate of
infusion) until a point after which the rate of elimination equals the rate of infusion i.e. the
concentration of drug in plasma approaches a constant value called as steady state, plateau or
infusion equilibrium.

 At steady-state, the rate of change of amount of drug in the body is zero hence the equation 3
becomes:
Zero = Ro – KE XSS
Therefore, KE XSS = Ro
R0 ……………….….(5)
C  
R0 i.e. Infusion rate
ss
K E Vd ClT Clearance

 Where, XSS and CSS are amount of drug in the body and concentration of drug in plasma at steady
state respectively.
 The value of KE (and hence t1/2) can be obtained from the slope of straight line obtained after a semi
logarithmic plot (log C versus T) of plasma concentration-time data gathered from the time when
infusion is stopped.
 Alternatively KE can be calculated from the data collected during infusion to steady state as follows:
Substituting Ro/ClT = CSS from equation 5 in equation 3 we get:
C = Css (1-e-ket)................ (6)

 Rearrangement yields: 

 C - C   -K t
 ss  e
E

 Css  ………….(7)
  Transforming to log form the equation becomes:
C - C  -K t
log  ss   E

 Css  2.303 ……….(8)

 A plot of log (Css 3 C) / Css versus t results in a straight line with slope 3KE/2.303

 The time to reach steady state concentration is dependent upon the elimination half life and not
infusion rate.
 An increase in infusion rate will merely increase the plasma concentration attained at steady state.
 If n is the number of half-lives passed since the start of infusion (t/t1/2), equation 6 can be written as
C = CSS [1 – (1/2)n]………(9)
Infusion plus Loading Dose
 It takes a very long time for the drugs having longer half-lives before the plateau concentration is
reached (e.g. Phenobarbital, 5 days).
 This can be overcome by administering an IV loading dose large enough to yield the desired steady
state immediately upon injection prior to starting the infusion.
 It should then be followed immediately by IV infusion at a rate enough to maintain this
concentration.
  Recalling once again the relationship X = Vd C, the equation for computing the loading dose XO,L
can be given:
XO,L = CSS Vd
 Substitution of CSS = Ro/KEVd from equation 37 in above equation yields another expression for
loading dose in terms of infusion rate:
XO,L = Ro / KE
 The equation describing the plasma concentration-time profile following simultaneous i.v. loading
dose (i.v. bolus) and constant rate i.v. infusion is the sum of two equations describing each process.

One-Compartment Open Model

 Extravascular Administration
 When a drug is administered by extra vascular route (e.g. oral, rectal, etc.) absorption is a
prerequisite for its therapeutic activity.
 Absorption kinetics of drug may be first order or it may be zero order kinetics in rare cases.

 Zero order absorption is characterized by a constant rate of absorption. It is independent of amount

of drug remaining to be absorbed (ARA), and its regular ARA versus t plot is linear with slope equal
to rate of absorption while the semilog plot is described by an ever increasing gradient with time.
  In contrast, the first order absorption process is distinguished by a decline in the rate with ARA i.e.
absorption rate is dependent upon ARA; its regular plot is curvilinear and semilog plot of a straight
line with absorption rate constant as its slope.
 After extravascular administration, the rate of change in amount of drug in the body dX/dt is the
difference between the rate of input (absorption) dXev/dt and rate of output (elimination) dXE/dt
dX/dt = Rate of absorption – Rate of elimination

dx / dt = dxa / dt – dxe / dt .............(1)

 During the absorption phase, the rate of absorption is greater than the rate of elimination
dxa / dt > dxe / dt ............... (a)
 At peak plasma concentration, the rate of absorption equals the rate of elimination and the change
in amount of drug in the body is zero
dxa / dt = dxe / dt ................ (b)
 During the post absorption phase, there is some drug at the extravascular site still remaining to be
absorbed and the rate of elimination at this stage is greater than the absorption rate.
dxa / dt < dxe / dt.................. (c)
 After completion of drug absorption, its rate becomes zero and the plasma level time curve is
characterized only by the elimination phase.

Zero-Order Absorption Model

 This model is similar to that for constant rate infusion.
 Example of zero order absorption, rate of drug absorption for controlled drug delivery systems.
  All equations that explain the plasma concentration-time profile for IV infusion are also applicable to
this model.

First-Order Absorption Model

 For a drug that enters the body by a first-order absorption process, gets distributed in the body
according to one-compartment kinetics and is eliminated by a first-order process, the model can be
depicted as follows:

 The differential form of the equation

dX
 K aX a - KEX
dt …………(2)
where, Ka = first-order absorption rate constant, and
Xa = amount of drug at the absorption site remaining to be absorbed i.e. ARA.
 Integration of equation 1 yields:
X = Ka F Xo [e-Ket – e-Kat] ............... (3)
(Ka-KE )
 Transforming into concentration terms, the equation becomes:
C = Ka F Xo [e-Ket – e-Kat] ............. (4)

Vd (Ka-KE)

Assessment of Pharmacokinetic Parameters

Cmax and Tmax:
 At peak plasma concentration KaXa = KEX and the rate of change in plasma drug concentration
dC/dt = 0.
 On simplifying, the above equation becomes:
KE e-Ket = Ka e-Kat.................. (5)
 Converting to logarithmic form,
 ………(6)
 where t is tmax. Rearrangement of above equation yields:

………..(7)
 Cmax can be obtained by substituting equation 7 in equation 4.

………….(8)
 It has been shown that at Cmax, when Ka = KE, tmax = 1/KE. Hence, the above equation further
reduces to:

………….(9)
Elimination Rate Constant:
 This parameter can be computed from the elimination phase of the plasma level time profile.
 For most drugs administered extravascularly, absorption rate is significantly greater than the
elimination rate i.e. Kat>>>KEt.
 Hence one can say e3Kat approaches zero must faster than does e3KEt.
 The stage at which absorption is complete, change in plasma concentration is dependent on
elimination rate and equation 4 reduces to:

………….(10)
 Transforming to log form the equation becomes:

…………(11)
 A plot of log C versus t yields a straight line with slope 3KE/2.303 (therefore, t1/2= 0.693/KE).
Question: Describe the method of residuals for determination of absorption rate constant Draw an
illustrative diagram for that.

Determination of Absorption Rate Constant (Ka):

 It can be calculated by method of residuals.
 This technique is also known as feathering, peeling and stripping.
 It is commonly used in pharmacokinetics to resolve a multiexponential curve into its individual
components.
 For a drug, that follows one compartment kinetic and administered extravascularly, the concentration
of drug in plasma is expressed by a biexponential equation 4:

………….(12)
 IF Ka F XO / Vd (Ka -KE) = A a hybrid constant, then: 

C = A [e-KEt - e-Kat]............... (13)

 During the elimination phase, when absorption is almost over Ka >>> KE and the value of second

exponential e3Kat approaches zero whereas the first exponential e3KEt retains some finite value. At
this time equation 13 reduces to:

………………(14)

 In log form above equation can be written as:

………….(15)
 Where log C represents the back extrapolate plasma concentration values.
 A plot of log C versus t yields a biexponential curve with a terminal linear phase having slope 3
KE/2.303 (figure 1).
 Back extrapolation of this straight line to time zero yields y-intercept equal to log A.
  Substraction of true plasma concentration value i.e. equation 13 from the extrapolated plasma
concentration values i.e. equation 14 yields a series of residual concentration values Cr:

…………(16)
In log form the equation is:

…………..(17)
 A plot of log Cr versus t yields a straight line with slope 3Ka/2.303 and Y intercept log A.
(Question: Explain Wagner nelson method in detail.)

Wagner-Nelson Method for Estimation of Absorption Rate Constant (Ka):

 One of the better alternatives to curve fitting method in the estimation of Ka is Wagner-Nelson
method.
 The method involves the determination of Ka from percent unabsorbed time plots and does not
require assumption of zero or first order absorption.
 After oral administration of a single dose of a drug, at any given time, the amount of drug absorbed
into the systemic circulation X A, is the sum of amount of drug in the body X and the amount of drug
eliminated from the body XE. Thus

XA = X + XE......................... (1)
 The amount of drug in the body is X=Vd C. The amount of drug eliminated at any time t can be
calculated as follows:
X E = KEVd [ AUC ]0 t .......................... (2)
 Substitution of values of X and XE in equation 1 yields:

XA = VdC + KEVd [ AUC ]0 t ..................... (3)

 The total amount of drug absorbed into systemic circulation from time zero to infinity X A∞ can be
given as:

XA ∞ = V dC ∞ + K EV d [ AUC ] 0 ∞………(4)
 Since at t = ∞, C∞ = 0, the above equation reduces to:

XA ∞ = KE Vd [ AUC ]0 ∞ .............. (5)

 The fraction of drug absorbed at any time t is given as:

………(6)
 Percent drug unabsorbed at any time is therefore:

……………….(7)
  This method requires collection of blood samples after a single oral dose at regular intervals of time
till the entire amount of drug is eliminated from the body.

 KE is obtained from plot of log C versus t and [AUC] 0 t and [AUC] 0 ∞ are obtained from plots of C
versus t.
 A semi log plot of percent unabsorbed (i.e. percent ARA) versus t yields a straight line whose slope
is 3Ka/2.303(figure 1). If a regular plot of the same is a straight line, the absorption is zero order. Ka
can similarly be estimated from urinary excretion data.
 The biggest disadvantage of Wagner-Nelson method is that it applies only to drugs with one-
compartment characteristics.
 Problem arises when a drug that obeys one compartment model after extra vascular administration
shows multicompartment characteristics on IV injection.

Question: Give the criteria for obtaining valid urinary excretion method. What are the merits and
demerits of using urinary excretion data for pharmacokinetic parameters?

URINARY EXCRETION DATA

Advantages
 Useful when there is lack of sufficiently sensitive analytical techniques to measure concentration of
drug in plasma.
 Noninvasive method therefore better subject compliance.
 Convenience of collecting urine samples in comparison to drawing of blood periodically.
 If any case the urine drug concentration is low, assaying of larger sample volume is relatively more.
  Direct measurement of bioavailability, both absolute & relative is possible without the necessity of
fitting the data to the mathematical model.

Criteria for Obtaining Valid Urinary Excretion Data

1. A significant amount of drug must be excreted unchanged in the urine (at least 10%).
2. The analytical method must be specific for the unchanged drug; metabolites should not interfere.
3. Water-loading should be done by taking 400 ml of water after fasting overnight, to promote diuresis
and enable collection of sufficient urine samples.
4. Before administration of drug, the bladder must be emptied completely after 1 hour from water-
loading and the urine sample taken as blank. The drug should then be administered with 200 ml of water
and should be followed by 200 ml given at hourly intervals for the next 4 hours.
5. Volunteers must be instructed to completely empty their bladder while collecting urine samples.
6. Frequent sampling should be done in order to obtain a good curve.
7. During sampling, the exact time and volume of urine excreted should be noted.
8. An individual collection period should not exceed one biological half-life of the drug and ideally
should be considerably less.
9. Urine samples must be collected for at least 7 biological half-lives in order to ensure collection of
more than 99% of excreted drug.
10. Changes in urine pH and urine volume may alter the urinary excretion rate.

Question: Explain Sigma – Minus Method for determination of elimination rate constant.

Determination of KE from Urinary Excretion Data

The first-order elimination (and excretion) rate constants can be computed from urine data by two methods:
1. Rate of excretion method, and
2. Sigma-minus method.

Rate of Excretion Method:

 The rate of urinary drug excretion dXu/dt is proportional to the amount of drug in the body X and
written as:
dXu / dt = KE X .............. (1)
 Where, KE = first-order urinary excretion rate constant. According to first-order disposition kinetics,
X = Xo e3KEt. Substituting it in above equation yields:
 dXu / dt = KE XO e-KEt ................... (2)
 Where, Xo = dose administered (i.v. bolus). Transforming to log form the equation becomes:
log dXu / dt = log KE XO – KEt / 2.303 ............. (3)
 The above equation states that a semilog plot of rate of excretion versus time yields a straight line
with slope 3KE/2.303 (Fig.1).

Sigma-Minus Method:
 A disadvantage of rate of excretion method in estimating KE is that fluctuations in the rate of drug
elimination are observed to a high degree and in most instances, the data are so scattered that an
estimate of half-life is difficult. These problems can be minimized by using the alternative approach
called as sigma-minus method.

dXu / dt = KE XO e-KEt....................(1)

 Integration of equation 1 yields:

…………(2)
 Where, Xu = cumulative amount of drug excreted unchanged in urine at any time t.

 As time approaches infinity i.e. after 6 to 7 half-lives, the value e3KE∞ becomes zero and therefore

the cumulative amount excreted at infinite time Xu∞ can be given by equation:

Xu∞ = Ke X0 / KE.......................................(3)
 Substitution of equation 9.75 in equation 9.74 and rearrangement yields:
Xu∞ - Xu = Xu∞e-Ket ............... (4)
 Converting to logarithms, we get:
∞
log (Xu - Xu∞) = log Xu – KEt /2.303 ................... (5)

 where, (Xu 3 Xu) = amount remaining to be excreted i.e. ARE at any given
time. A semilog plot of ARE versus t yields a straight line with slope -KE/2.303.
The method is, therefore, also called as ARE plot method.