BASIC PHARMACOKINETICS - CHAPTER 11: Multicompartment Model

`PHARMACOKINETICS: MAMMILLARY MODELS
For many drugs, the equilibrium between drug concentrations in different tissues is not achieved
rapidly. Thus, one of the assumptions of the one-compartment open model sometimes becomes
invalid. A more complex mammillary open model is often necessary to describe mathematically
the plasma concentration data (for example) seen after the administration of some drugs. The
simplest mammillary open model is a two-compartment open model where the drug is both
introduced into and exits from the central compartment ; for example:
X0
k12
X1 X2
k21
k10
• Compartment One (X1, the central compartment) can be sampled through the blood
(or plasma, or serum). It may consist of organs or tissues which, being highly
perfused with blood, are in rapid equilibrium distribution with the blood.
• Compartment Two (X2, the peripheral compartment) cannot normally be sampled. It

may consist of organs or tissues which, being poorly perfused with blood, are in slow
equilibrium distribution with the blood.
• The Body is the sum of both compartments.
1. Intravenous Bolus Administration: Plasma Concentration Data

Recall that for a one-compartment open model, the plasma concentration follows the
equation:
Cp = Cp0 e( − kT ) (11.1.1)
Plasma Concentration vs. Time
1000
Plasma Concentration
100
10
0 5 10 15 20 25 30
Time
i.e., the
concentration of drug in the plasma declines mono-exponentially with time (one
straight line on semi-log paper.)
2. Bi-exponential Properties of Two-Compartment Open Model
Following an intravenous bolus injection, the plasma concentration against time profile
has two phases:
a. Initial phase - (α - phase)
b. Terminal phase - (β - phase)
Plasma Concentration vs. Time
1000
Alpha Phase
Plasma Concentration
Beta Phase
100
10
0 5 10 15 20 25 30
Time
On semilogarithmic paper (logarithm on the Y axis), the terminal phase is linear,

indicating that initial distribution has been completed and that equilibrium has
been attained. The terminal half life (T½β ) can be measured from the terminal
phase.
For a two-compartment open model, The plasma concentration follows the

equation:
Cp = A1e( ) + B1e( )
−α T − βT
(11.1.2)
i.e., the concentration of drug in the plasma declines bi-exponentially with

time.
2.1 Symbols
i. A1 and B1 are intercept constants (m/L3)

ii. α and β are hybrid rate constants (T-1)
iii. V1 is the apparent volume of unchanged drug distribution in compartment
1 (L3)
iv. k10, k12, and k21 are the “micro” rate constants (T-1)
2.2 Relationships:
1
2 (
α = ( k10 + k12 + k21 ) + ( k10 + k12 + k21 )
2
)
− 4 ( k10 k21 ) (11.1.3)
1
2 (
β = ( k10 + k12 + k21 ) − ( k10 + k12 + k ) − 4(k k ) )
21
2
10 21 (11.1.4)
D (α − k21 )
A1 = (11.1.5)
V1 (α − β )
D ( k21 − β )
B1 = (11.1.6)
V1 (α − β )
Cp0 = A1 + B1 (11.1.7)
α + β = k12 + k10 + k21 (11.1.8)
αβ = k10 k21 (11.1.9)
2.3 Obtaining Pharmacokinetic Parameters by “Feathering”

By convention, α > β
a. Plot Cp against t on semilogarithmic paper
b. Find t½ from the linear terminal phase: see “Intravenous
Administration,” section A1.4a
c. Calculate the terminal hybrid rate constant (β); in reality it
contains both distributive (k12 and k21) and elimination (k10)
factors.
ln(2)
β= (11.1.10)
(t 1 2 ) β
d. Draw a straight line through the linear terminal elimination phase

HJJ is equal to B1.
and extrapolate this line to t = 0. The intercept
e. Read extrapolated plasma concentrations C p from the plot at times
equal to those given for values of Cp which are prior to the
terminal phase.
f. At each of these times, calculate:
HJJ
C p diff = C p − C p (11.1.11)
g. Plot C p diff against t on semilogarithmic paper. The plot is a
“feathered” line and should decline linearly.
h. Find the half-life of the plot. It will refer to the initial phase.
Calculate,
ln(2)
α= (11.1.12)
(t 1 2 )α
i. Measure the intercept of the “feathered” line; it will be equal to A1

(note that A1 ≠ B1, even theoretically).
j. Calculate (Cp)o from Eq. (11.1.7)
k. Calculate V1 by
X0 Dose
V1 = = (11.1.13)
Cp0 A1 + B1
Theory (Why does feathering work?)
When t is large, e-αt < e-βt. Hence, Eq (11.1.2) becomes

Cp = B1e( − β T ) (11.1.14)
i.e., when t is large, the concentration of the drug in the plasma
declines exponentially with time.
The extrapolated plasma
HJJ
concentrations are
Cp = B1e( )
− βT
(11.1.15)
Substituting from Eqs. (11.1.2)and (11.1.15) into Eq.(11.1.11),
C pdiff = A1e( −αT ) (11.1.16)
i.e., the difference between observed and extrapolated drug
concentrations in the plasma declines exponentially with
time.
Note: The micro rate constants in terms of the graphical variables are:
α B1 + β A1
k21 = (11.1.17)
A1 + B1
αβ αβ ( A1 + B1 )
k10 = = (11.1.18)
k21 α B1 + β A1
A1 B1 (α − β )
2
k12 = α + β − k10 − k21 = (11.1.19)

(α B1 + β A1 )( A1 + B1 )
2.4 Clearance and Volume Concepts
If model-independent equations can be used to define these terms, this is
preferred.
a. Systemic Clearance (C1) may be calculated by,
Dose
Cl = (11.1.20)
AUC0∞
b. The volume terms are more complex than in a one-compartment
open model. There are two terms of interest:
The apparent volume of distribution in compartment one (V1) -
This is calculated using Eq.(11.1.15)
The apparent volume of distribution at pseudo-distribution
equilibrium (Vβ)
This volume may be defined only in relation to the terminal
phase (β-phase), when initial distribution has been
completed. It may be calculated by,
Dose
Vβ = (11.1.21)
β AUC0∞
As Vβ requires calculation of the total area under the
plasma concentration against time curve, it is also known
as Varea.
c. Comparing Eqs. (11.1.20)and (11.1.21),
Cl = βVβ (11.1.22)
It may also be shown that,
Cl = k10V1 (11.1.23)
This follows as systemic clearance is always given by the
elimination rate constant out of the body multiplied by the
apparent volume of distribution in the compartment from which
drug leaves the body. Comparing Eqs. (11.1.22) and (11.1.23),
k
Vβ = 10 V1 (11.1.24)
β
Note that k10 (the elimination rate constant) is not the same as β
(the terminal hybrid rate constant).
2.5 Bioavailability
Find (AUC)0 using trapezoidal rule and, if necessary, the calculation for
the terminal area.
tlast
Cp
AUC0∞ = ∑ AUC + last (11.1.25)
0 β
This is a model-independent equation.
2.6 Dosage Regimens

The maintenance dose (DoseM) is given by the same model-independent
equation as before,
DoseM = C p Clτ ( ) ss
(11.1.26)
( )
Where C p
ss
has its same previous definition.
The loading dose (DoseL) achieves a steady-state condition quite rapidly,
but only after initial distribution has been completed. It is given by the
previous equation,
DoseM
DoseL = (11.1.27)
()
N
1 − 12
( )
As may be expected, equations relating (Cmax)ss and (Cmin)ss to Cp
ss
are
as before.
All dosage regimen equations strictly apply only when,

β  k12 
1 +  ≈1 (11.1.28)
k10  k21 
Eq. (11.1.28) has the value of
0.947 for digoxin
0.990 for warfarin
0.846 for cephalexin
This is why, despite the fact that an open two-compartment model is the
better description of the pharmacokinetics of these drugs, a simple one-
compartment model may often be assumed for dosage regimen purposes.
3. Intravenous Bolus Administration: Compartment Two
It is not normally possible to measure drug concentrations in compartment two.
However, the mass of drug can be predicted based on the drug concentrations
observed in compartment one.
α −β
e (
k Dose ( − β T ) ( −α T )
X 2 = 12 −e ) (11.1.29)
Note that the equation form bears a similarity to that seen for plasma
concentrations after oral administration into a one-compartment open
model.
When t is large, e-αt < e-βt. Hence, Eq. (11.1.29) becomes,

k Dose ( − β T )
X 2 = 12
α −β
e ( ) (11.1.30)
This is compared to the mass modification of Eq.(11.1.14),

X 1 = V1 B1e( )
− βT
(11.1.31)
Thus, when t is large, the masses of drug in each compartment decline
exponentially, and in parallel, with time. This indicates that equilibrium attained.
If the value of X2 reflects drug concentrations at the active site, the time of
maximum concentration (and maximum pharmacological effect) is:
 
Ln  αβ 
tmax =  
(11.1.32)
α −β
4. Other Dosage Forms
The equations become complex and it is therefore difficult to obtain useful

parameter values without the aid of a computer. Fortunately, because the
complexity of the equations is greater than the experimental accuracy of the
assays warrants, drugs that strictly require a mammillary model can be described
adequately by an open one-compartment model for the purposes of calculating
dosage regimens.
4.1 Intravenous Infusion
The plasma concentrations at first rise faster than an open one-

compartment model profile would suggest. Later, the rise is slower. The
decline, following the cessation of infusion, is bi-exponential.
Cp =
Q

(
 ( k21 − β ) 1 − e − β t
−
) (
( k21 − α ) 1 − e−α t )  (11.1.33)
V1 (α − β )  β α 

Where α is as before in equation (11.1.3)

β is as before in equation (11.1.4)
Q is the infusion rate
V1 is as before in equation (11.1.2)
Cpss would be given by setting time equal to infinity and reducing
equation (11.1.33) to
Q Q
Cpss = = (11.1.34)
V1k10 Clearance
If theer infusion was terminated at time T, the concentration at time T

would be given by substituting T for t in equation (11.1.33) and the
concentration after time T would be given by
Cp =
Q

( −
) (
 ( k21 − β ) e β T − 1 e − β t ( k21 − α ) eαT − 1 e−α t 

) (11.1.35)
V1 (α − β )  β α 

4.2 Oral Administration
100
Concentration
10
0 2 4 6 8 10 12
Time
At a time just after tmax the plasma concentration may exhibit a “nose,” when
compared to the profile of an open one-compartment model if the absorption
rate is significantly larger than α and β . The terminal rate constant will be
reflected by the smallest rate constant usually β but sometimes it could be Γ,
the absorption rate constant.
Cp = A1e −α t + B1e − β t + C1e −γ t (11.1.36)

Where α is as before in equation (11.1.3)
β is as before in equation (11.1.4)
γ = ka, the absorption rate constant
D ( k21 − α ) γ
A1 = (11.1.37)
V1 ( γ − α )( β − α )
D ( k21 − β ) γ
B1 = (11.1.38)
V1 ( γ − β )(α − β )
D ( k21 − γ ) γ
C1 = (11.1.39)
V1 (α − γ )( β − γ )
Cp0 = A1 + B1 + C1 = 0 (11.1.40)
SELECTED REFERENCES
Riegelman, S., Loo, J.C.K., and Rowland, M., Shortcomings in pharmacokinetic analysis by
conceiving the body to exhibit properties of a single compartment, J. Pharm. Sci., 57, 117-123
(1968).
Riegelman, S., Loo, J.C.K., and Rowland, M., Concept of a volume of distribution and possible
errors in evaluation of this parameter, J. Pharm.Sci., 57, 128-133 (1968).
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharmacokinetics, J. Pharm. Sci., 58, 639-641
(1969).
Gibaldi, M., Nagashima, R., and Levy, G., Relationship between drug concentrations in plasma
or serum and amount of drug in the body, J. Pharm.Sci., 58, 193-197 (1969).
Metzler, C.M., Usefulness of the two-compartment open model in pharmacokinetics, J. Amer.

Stat. Assn., 66, 49-54 (1971).
Gibaldi, M. and Perrier, D., Drug elimination and apparent volume of distribution in
multicompartment systems, J. Pharm. Sci., 61, 952-954 (1972).
Gillette, J.R., The importance of tissue distribution in pharmacokinetics, J. Pharmacokin.

Biopharm., 1, 497-520 (1973).
Drug Disposition: Volume Terms
As apparent volumes of distribution are proportionality constants, and not physilological spaces,
more than one term is of value.
1. Apparent Volume of sampled compartment (V1)
This relates the concentration of drug on the sampled compartment with the mass of drug
in that compartment.
It may be calculated after an intervenous dose by:

Dose Dose
V1 = = (11.2.1)
K ( AUC )
∞
C p0
0
It may be calculated after an intervenous infusion by

X Q
V1 = 1ss = (11.2.2)
(
C pss K C p
ss
)
2. Apparent Volume at Pseudo-Distribution Equilibrium (Vβ)
This volume term (sometimes known as the apparent volume of distribution of the drug
in the body) requires the assumption that the drug is evenly distributed throughout the
body which is clearly not true in most cases. Thus Vβ is only defined in relationship to
the terminal phase (β phase) after equilibrium has been attained. It is calculated by:
Dose
Vβ = (11.2.3)
β ( AUC )0
∞
3. Relationships between apparent volumes:

Clearance (Cl) is calculated by the first order rate constant for the removal of the drug
from the body multiplied by the volume of distribution of the drug in the compartment
from which the drug leaves the body:
Clr = krV1 (11.2.4)
Clm = kmV1 (11.2.5)
Cls = KV1 (11.2.6)
However, systemic clearance is calculated by:

Dose
Cls = (11.2.7)
( AUC )0
∞
Comparing Eqs (11.2.3) and (11.2.7) we find:

Cls = βVβ (11.2.8)
And comparing Eqs (11.2.6) and (11.2.8) we find
K
Vβ = V1 (11.2.9)
β
As K > β, then Vβ >> V1. Note that if the pharmacokinetics cam be described by the one
compartment model, then β = K and Vβ = V1.
Selected References
Riegelman, S., Loo, J.C.K. and Rowland, M., Concept of volume of distributions and possible
errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133 (1968)
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharmacokinetics, J. Pharm. Sci. 58, 639-641
(1969)
Gibaldi, M., Nagashima, R., and Levy, G., Relationship between drug concentrations in plasma
or serum and the amount of drug in the body. J. Pharm. Sci., 58, 193-197 (1969)
Perrier, D. and Gibaldi, M., Relationship between plasma or serum drug concentrations and the
amount of drug in the body at steady state upon multiple dosing, J. Pharmacokin. Biopharm., 1,
17-22 (1973)
Oie, S. and Tozer, T.N., Effect of altered plasma protein binding on apparent volumes of
distribution, J. Pharm. Sci., 68, 1203-1205 (1979)
Linear Mamillary Models and the LaPlace Transform
Drug is usually sampled from the central compartment, designated as compartment one.
1. Laplace transform for Compartment One
As ,1 = (in)(d s ,1 ) (11.3.1)
Where:
A s,1 is the Laplace transform for the mass of the drug in
compartment one
s is the Laplace Operator
in is the input function
ds,1 is the disposition function for compartment one.
2. Input functions
(Note: Input need not be into compartment one)
a. IV Bolus
(in) = D (11.3.2)
Where: D is the dose.
b. IV Infusion
Q(1 − e − sb )
(in) = (11.3.3)
s
Where: Q is the zero oder infusion rate,
b =t when t<Term
b=T when t>=Term
and Term is the termination time of the infusion
c. First order absorption

ka FD
( in ) = (11.3.4)
( s + ka )
Where: ka is the first order absorption rate constant
F is the fraction of the dose that ultimately reaches
systemic absorption.
d. Dissolution and absorption (Type 1)

kr ka FD
( in ) = (11.3.5)
( s + kr )( s + ka )
Where: kr is the first order dissolution rate constant
e. Dissolution and absorption (Type 2)

k k (1 − e − sb )
( in ) = 0 a (11.3.6)
s ( s + ka )
Where: k0 is the zero order dissolution rate constant, ceasing at
time T
f. Others
More complex functions can be derived simply by the serial addition of the above
functions, e.g.:
Q(1 − e − sb )
(in) = D + (11.3.7)
s
Denote the simultaneous commencement of an IV bolus and IV infusion.
3. Disposition Function for Compartment One

A driving force compartment has one or more exit rate constants; for example, in
compartment i, the sum of the first order rate constants is Σi. Then:
i=n
kq1 ∏ ( s + Σi )
i=2
(d ) =
s ,1
i≠q
 
(11.3.8)
i=n j =n m=n
 
∏ ( s + Σ i ) − ∑ 
j =2 
k1 j j1 ∏ ( s + Σ m ) 
k
i =1 m=2 
 m≠ j 
Where: q is the compartment into which the input
occurs
n is the number of driving force compartments
i,j are counters (maximum of n)
kq1 is the first order rate constant for transfer of
drug from the input compartment into
compartment one
k1j, kj1 are the first order rate constants for drug
transfer from compartment one to
compartment j and visa versa.
a. Using the disposition function:

i. If q = 1, then kq1 = 1
ii. Πi and Πm are continued products. The value equals one when the
counter I or m takes on a forbidden number. For example i=1 is
forbidden in the numerator and m=1 and m=j are forbidden in the
denominator.
b. Examples
i. One compartment open model (n=1,q=1)
d s ,1 = 1 (11.3.9)
ii. Two compartment open models (n=2,q=1)
d s ,1 =
( s + Σ2 ) (11.3.10)
( s + Σ1 )( s + Σ 2 ) − k12 k21
iii. Three compartment open models (n=3,q=2)
k21 ( s + Σ3 )
d s ,1 = (11.3.11)
( s + Σ1 )( s + Σ 2 )( s + Σ3 ) − k12 k21 ( s + Σ3 ) − k13k31 ( s + Σ 2 )
c. Simplifying the denominator
The number of exponential terms in the final integrated equation will be equal to
the number of driving force compartments (n.) This is also equal to the maximum
power to which the LaPlace operator (s) would appear if the denominator were
i =n
multiplied out. Hence, the denominator is simplified to become ∏ ( s + k ) where
i =1
i
ki is a composite rate constant. Thus for the:

One compartment model:
1
d s ,1 = (11.3.12)
( s + k1 )
Two compartment models
d s ,1 =
( s + Σ2 ) (11.3.13)
( s + k1 )( s + k2 )
Three compartment models
k21 ( s + Σ3 )
d s ,1 = (11.3.14)
( s + k1 )( s + k2 )( s + k3 )
The exact meaning of ki for any model depends on the equalities evident in the
denominators.
For example for the two compartment model
( s + k1 )( s + k2 ) = ( s + Σ1 )( s + Σ 2 ) − k12 k21 (11.3.15)
And the right side of equation (11.3.15) can be multiplied out to the resultant
quadratic equation as 2 + bs + c which is subsequently factored using the equation
−b ± b 2 − 4ac
to solve for the roots of a quadratic equation ki =
2a
4. Method of partial fractions
This method is used to solve the LaPlace transform provided that there are NO repeating
factors in the denominator. E.g. NO s2 or (s+ki)2.
a. Prepare the LaPlace transform, e.g. IV Bolus into the two compartment model:
D ( s + Σ2 )
as ,1 = (11.3.16)
( s + k1 )( s + k2 )
b. Obtain the roots
For (s+k1) the root is –k1
For (s+k2) the root is –k2
If the factor is s the root is 0.
c. The “Hidden Hand” Method

i. Deal with each factor in turn.
ii. Cover each factor and remember its root.
iii. Whenever the LaPlace operator occurs in the uncovered transform,
substitute the root for s
iv. Multiply the result by est, again substituting the root for s.
v. After doing 2 through 4 for each factor, simplify.
For the two compartment model the result would be:
D ( − k1 + Σ 2 ) − k1t D ( − k2 + Σ 2 ) − k 2t
X1 = e + e (11.3.17)
( −k1 + k2 ) ( −k2 + k1 )
which can take the form of:
C1 = A1e −α t + B1e − β t (11.3.18)
with the exact meanings of the variables dependent on the form of the
model.
5. LaPlace Transfom for peripheral compartments

This is analogous to that of employed when using the LaPlace transform table.
a. Draw the model.
b. Write the differential equation using all the arrows which touch the box
(compartment) in question.
c. Take the transform of each side of the equation using the table where necessary.
d. Use algebra to get the single time dependent variable on the left side and
everything else on the right side.
e. Substitute for any know transformed dependent variables on the right side of the
equation.
f. Solve using the “Hidden Hand” method above and simplify.
6. Method if the denominator contains the factor s2.

The “Hidden Hand” method is not applicable for the factor s2 as it has no simple root.
The S2 factor may show up in terminal compartments, such as urine, following an IV
infusion.
a. Example (n=2,q=1, exit from compartment one)
(
as ,u = k10Q 2
)
1 − e − sb ( s + Σ 2 )
(11.3.19)
s ( s + k1 )( s + k2 )
where: k10 is the first order excretion rate constant from
compartment one.
and this results in:
Σb
X u = k10Q 2 + .... (11.3.20)
k1k2
where Xu is the cumulative mass of drug excreted into the urine
and the other factors are handled by the “Hidden Hand” method as
above.
b. Example (n=3,q=1, exit from compartment one)
as ,u = k10Q 2
( )
1 − e − sb ( s + Σ 2 )( s + Σ3 )
(11.3.21)
s ( s + k1 )( s + k2 )( s + k3 )
and this results in:
ΣΣb
Xu = k10Q 2 3 + ... (11.3.22)
k1k2 k3
References
L.Z.Benet, General treatment of linear mamilary models with elimination from any compartment
as used in pharmacokinetics, J. Pharm. Sci., 61 536-541 (1972)
D.P. Vaughan, D.J.H. Mallard, A. Trainor, and M. Mitchard, General pharmacokinetic equations
for linear mammillary models with drug absorption into peripheral compartments, Europ. J. Clin.
Pharmacol., 8, 141-148 (1975)
D.P. Vaughn and Trainor, Derivation of general equations for linear mammillary models when
drug is administered by different routes, J/ Pharmacokin. Biopharm., 3, 203-218 (1975)
Aspirin
Fu, C., Melethil, S., and Mason, W., "The pharmacokinetics of aspirin in rats and the effect of
buffer", Journal of Pharmacokinetics and Biopharmaceutics, Vol. 19, (1991), p. 157 - 173.
Aspirin is an analgesic/ antipyretic commonly used to relieve minor pain and is

used in such conditions as rheumatic fever, rheumatoid arthritis, and osteoarthritis. The
major metabolite of aspirin is salicylic acid. The following set of data was collected
using rats which weighed 250 - 300 g. Graph the data and find A1, α, B1, β. Check
your answers with the answers given below and answer the remaining questions using
the correct answers.
Time(hr) Time(min) Cp(mg/L)
0.000 0.000 15.820
0.001 0.065 15.152
0.005 0.324 12.853
0.011 0.648 10.650
0.022 1.296 7.732
0.032 1.943 5.981
0.058 3.466 3.830
0.116 6.931 1.815
0.173 10.397 0.905
0.289 17.329 0.226
0.433 25.993 0.040
0.578 34.657 0.007
weight of rat 275 g
Dose 5 mg/kg IV
µg
A1 8.58
mL
α 1.07 min −1
µg
B1 7.24
mL
β 0.2 min −1
µg
AUC 38.8 ⋅ min
mL
AUMC µg
116.0 ⋅ min 2
mL
1. What is AUCα ?
2. What is AUCβ ?
3. What is your patient's clearance?
4. What is your patients MRT?
5. What is your patient's Vβ ?
6. What is your patient's V1?
7. What is your patient's Vd ss ?
8. What is t 1 2 (α ) ?
9. What is t 1 2 ( β ) ?
10. What is k21 ?
11. What is k10 ?
12. What is k12 ?
13. What is Cpo ?
14. What is the t max in the peripheral compartment?
15. What percent of the dose is in the peripheral compartment at equilibrium?
16. Can this drug be treated as a one-compartment model for dosing purposes?
17. If this drug can be treated as a one-compartment model, what is K ?
18. What would be the Cpmax and Cpmin if the patient were dosed as above by IV
bolus every four hours?
Buprenorphine
Ohtani, M., et al., "Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and
its active metabolite, norbuprenorphine, in rats", Drug Metabolism and Disposition, Vol. 22,
(1994), p. 2 - 7.
Buprenorphine is a morphine derivative which has twice the duration of action

and 30 times the potency of morphine. Buprenorphine is partially metabolized to
norbuprenorphine which is also active in the body. In this study, buprenorphine was
given to rats weighing 280 - 300 g. Graph the data and find A1, α, B1, β. Check your
answers with the answers given below and answer the remaining questions using the
correct answers.

0.000 0.000 0.051
0.018 1.069 0.048
0.089 5.346 0.039
0.178 10.691 0.030
0.356 21.382 0.019
0.535 32.074 0.014
2.558 153.464 0.005
5.115 306.929 0.003
7.673 460.393 0.001
Weight of rat 290 g
Dose 0.06 mg/kg IV
ng
A1 41
mL
α 3.89 hr −1
ng
B1 10
mL
β 0.271 hr −1
ng
AUC 48.3 ⋅h
mL
AUMC ng 2
135.24 ⋅h
mL
1. What is AUCα ?
2. What is AUCβ ?
4. What is your patients MRT?
8. What is t 1 2 (α ) ?
9. What is t 1 2 ( β ) ?
10. What is k21 ?
11. What is k10 ?
12. What is k12 ?
13. What is Cpo ?
Caffeine
Shi, J., et al., "Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor
effects", Clinical Pharmacology and Therapeutics, Vol. 53, (1993), p. 6 - 14.
This study looks at the cardiovascular effects of caffeine. Caffeine is known to

increase blood pressure upon its withdrawl. This study looks at how tolerance to
caffeine and its pressor effects develops and disappears with time. Graph the data and
find A1, α, B1, β. Check your answers with the answers given below and answer the
remaining questions using the correct answers.

0.000 0.000 19.650
0.014 0.849 18.914
0.071 4.244 16.413
0.141 8.488 14.084
0.283 16.975 11.164
0.424 25.463 9.573
3.014 180.821 4.550
6.027 361.642 2.275
9.041 542.463 1.138
15.068 904.105 0.284
22.603 1356.158 0.050
30.137 1808.210 0.009
Patient weight 80 kg
Dose 4 mg/kg oral
µg
A1 10.55
mL
α 4.9 hr −1
µg
B1 9.1
mL
β 0.23 hr −1
f 98.4 %
1. What is AUCα ?
2. What is AUCβ ?
3. What is AUCtotal ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Cefazolin
Nightingale, C., et al., "Changes in pharmacokinetics of cefazolin due to
stress", Journal of Pharmaceutical Sciences, Vol. 64, (1975), p. 712 - 714.
Cefazolin is a cephalosporin antibiotic used in the treatment of many types of

infections. This study looks at the effect of stress on the pharmacokinetics of cefazolin.
The following data was approximated from the graph given in this article. Graph the
data and find A1, α, B1, β. Check your answers with the answers given below and
answer the remaining questions using the correct answers.

0.000 0.000 329.440
0.014 0.861 314.606
0.072 4.303 264.012
0.143 8.607 216.497
0.287 17.214 155.940
0.430 25.821 121.899
1.210 72.581 62.078
2.419 145.162 30.742
3.629 217.743 15.370
6.048 362.904 3.843
9.073 544.356 0.679
12.097 725.809 0.120
Patient weight 56.3 kg
Dose 1 g IV
µg
A1 206.48
mL
α 4.832 hr −1
µg
B1 122.96
mL
β 0.573 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Ceftazidime
Ackerman, B., et al., "Effect of decreased renal function on the pharmacokinetics of
ceftazidime", Antimicrobial Agents and Chemotherapy, Vol. 25, (1984), p. 785 - 786.
Ceftazidime is a cephalosporin antibiotic. This study explores the effect of

compromised renal function on the pharmacokinetics of ceftazidime. The following data
was approximated from the graph given in this article. Graph the data and find A1, α,
B1, β. Check your answers with the answers given below and answer the remaining
questions using the correct answers.
Time(hr)Time(min) Cp(mg/L)
0.000 0.000 246.200
0.008 0.506 233.370
0.042 2.530 189.946
0.084 5.059 149.844
0.169 10.119 100.584
0.253 15.178 74.915
1.415 84.875 29.102
2.829 169.750 14.550
4.244 254.625 7.275
7.073 424.376 1.819
10.609 636.564 0.322
14.146 848.752 0.057
Dose 1 g IV bolus
mg
A1 188
L
α 8.22 hr −1
mg
B1 58.2
L
β 0.49 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
2-Chloro-2-deoxyadenosine
Liliemark, J. and Juliusson, G., "On the pharmacokinetics of 2-Chloro-2-deoxy-
adenosine in humans", Cancer Research, Vol. 51, (1991), p. 5570 - 5572.
Two-Chloro-2-deoxyadenosine is an antitumor agent used in the treatment of

hairy cell leukemia and other lymphoproliferative diseases. Infusions of 0.14 mg/kg
over 12 hours were administered to 12 patients with various lymphoproliferative
diseases for 5 consecutive days. Answer the remaining questions given this analysi of
the data.
Dose 0.14 mg/kg over 12 hours
A1 177.0 nM
α 1.04 hr −1
B1 21.0 nM
β 0.10 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Clentiazem
Shah, A., et al., "Pharmacokinetics of clentiazem after intravenous and oral administration in
healthy subjects", Journal of Clinical Pharmacology, Vol. 33, (1993), p. 354 - 359.
Clentiazem is an derivative of diltiazem which is under investigation for its use in

the treatment of angina pectoris and hypertension. Clentiazem blocks calcium channels
resulting in a decrease in peripheral vascular resistance which subsequently leads to a
decrease in blood pressure. Graph the data and find A1, α, B1, β. Check your answers
with the answers given below and answer the remaining questions using the correct
answers.
0.000 0.000 0.054
0.026 1.540 0.051
0.128 7.702 0.043
0.257 15.403 0.035
0.513 30.807 0.025
0.770 46.210 0.020
8.887 533.190 0.008
17.773 1066.380 0.004
26.660 1599.570 0.002
44.433 2665.951 0.001
Dose 20 mg IV bolus
ng
A1 37.52
mL
α 2.7 hr −1
ng
B1 16.17
mL
β 0.078 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Cocaine
Levine, B. and Tebbett, I., "Cocaine pharmacokinetics in ethanol-pretreated rats", Drug
Metabolism and Disposition, Vol. 22, (1994), p. 498 - 500.
This study looks into several reports which claim that the euphoric effects of
cocaine can be enhanced when taken in conjunction with alcohol. This effect may be
the result of higher cocaine blood levels or a reduced elimination of cocaine or a
combination of both. Graph the data and find A1, α, B1, β. Check your answers with
the answers given below and answer the remaining questions using the correct
answers.
0.000 0.000 1.635
0.003 0.191 1.556
0.016 0.957 1.291
0.032 1.915 1.048
0.064 3.830 0.754
0.096 5.744 0.607
15.403 924.196 0.231
30.807 1848.392 0.116
46.210 2772.589 0.058
77.016 4620.981 0.014
115.525 6931.472 0.003
Weight of rat
Dose 2 mg/kg cocaine
(also 1 g/ kg ethanol)
ng
A1 1172.6
mL
α 0.362 min −1
ng
B1 462
mL
β 0.045 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
1,2-Diethyl-3-Hydroxypyridine-4-One
Epemolu, O., et al., "The pharmacokinetics of 1,2-Diethyl-3-Hydroxypyridine-4-One
(CP94) in rats, Drug Metabolism and Disposition, Vol. 20, (1992), p. 736 - 741.
1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) is an iron chelator which is orally

active. It is being investigated for use in the treatment of hemoglobinopathic disorders.
In this study, rats weighing 250 - 300 g were given doses 50 mg /kg intravenously and
the following data was collected: Graph the data and find A1, α, B1, β. Check your
correct answers.
0.000 0.000 39.030
0.034 2.049 36.856
0.171 10.244 29.469
0.341 20.487 22.591
0.683 40.974 13.997
1.024 61.461 9.371
1.824 109.444 4.827
3.648 218.889 2.051
5.472 328.333 1.017
9.120 547.221 0.254
13.681 820.832 0.045
18.241 1094.443 0.008
Weight of rat 275 g
Dose 50 mg/kg IV
mg
A1 30.9
L
α 2.03 hr −1
mg
B1 8.13
L
β 0.38 hr −1
Assume that the rat ( which weighs 275 g) is suffering from thalassemia and his
iron levels are very high. The rat is prescribed CP94 to restore the iron levels to normal.
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
2,2-dimethylaziridine
Lalka, D., Jusko, W., and Bardos, T., "Reactions of 2,2-dimethylaziridine-type alkylating agents
in biological systems II: Comparative pharmacokinetics in dogs", Journal of Pharmaceutical
Sciences, Vol. 64, (1975), p. 230 - 235.
The 2,2-dimethylaziridine alkylating agents are used for their antitumor capability
as antineoplastic agents. In this study, male mongrel dogs, weighing 20 - 28 kg, were
each given a dose of 12 mg/kg of ethyl bis (2,2-dimethylaziridinyl) phosphinate
intraveneously. Graph the data and find A1, α, B1, β. Check your answers with the
answers given below and answer the remaining questions using the correct answers.
0.000 0.000 50.500
0.003 0.169 47.552
0.014 0.847 37.541
0.028 1.695 28.236
0.056 3.389 16.660
0.085 5.084 10.494
0.122 7.296 6.374
0.243 14.593 2.232
0.365 21.889 1.068
0.608 36.481 0.266
0.912 54.722 0.047
1.216 72.963 0.008
Weight of dog 24 kg
Dose 12 mg/kg IV
µg
A1 42
mL
α 0.409 min −1
µg
B1 8.5
mL
β 0.095 min −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Flurbiprofen
Menzel-Soglowek, S., et al., "Variability of inversion of (R)-flurbiprofen in different species",
Journal of Pharmaceutical Sciences, Vol. 81, (1992), p. 888 - 891.
Flurbiprofen is an anti-inflammatory and analgesic agent. This study compares

the pharmacokinetics of the (R)-isomer of flurbiprofen to the those of the (S)-isomer.
The following data was approximated from the graph given in this article. Graph the
data and find A1, α, B1, β. Check your answers with the answers given below and
answer the remaining questions using the correct answers.
0.000 0.000 107.180
0.030 1.785 103.627
0.149 8.925 91.467
0.297 17.849 79.953
0.595 35.699 65.003
0.892 53.548 56.258
3.961 237.650 29.345
7.922 475.301 14.670
11.883 712.951 7.335
19.804 1188.252 1.834
29.706 1782.378 0.324
39.608 2376.505 0.057
Weight of rat 260 g
Dose 10 mg/kg IV
mg
A1 48.5
L
α 2.33 hr −1
mg
B1 57.68
L
β 0.175 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Furosemide
Tilsone, W., and Fine, A., "Furosemide kinetics in renal failure", Clinical Pharmacology and
Therapeutics, Vol. 23, (1978), p. 644 - 650.
Furosemide is an agent which is used for its diuretic action to treat such
conditions as renal and cardiac edema. In this study, normal subjects were given an
intravenous bolus dose of 22 mg of furosemide. Blood samples were taken at various
intervals and the following data was obtained: Graph the data and find A1, α, B1, β.
Check your answers with the answers given below and answer the remaining questions
using the correct answers.
0.000 0.000 2.870
0.010 0.603 2.722
0.050 3.014 2.219
0.100 6.027 1.749
0.201 12.055 1.160
0.301 18.082 0.839
0.722 43.322 0.399
1.444 86.643 0.193
2.166 129.965 0.096
3.610 216.608 0.024
5.415 324.913 0.004
7.220 433.217 0.001
Dose 22 mg IV
mg
A1 2.1
L
α 6.9 hr −1
µg
B1 0.77
mL
β 0.96 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Glycyrrhizin
Tsai, T., et al., "Pharmacokinetics of glycyrrhyzin after intravenous administration to rats",
Journal of Pharmaceutical Sceinces, Vol. 81, (1992), p. 961- 963.
Glycyrrhizin is a component of licorice which is proposed to have anti-

inflammatory, anti-hepatotoxic, interferon-inducing, anti-viral, and anti-ulcer activity. It
also causes pseudoaldosteronism. The following data was approximated from the
graph given in this article. Graph the data and find A1, α, B1, β. Check your answers
answers.
0.000 0.000 161.130
0.017 1.000 154.522
0.083 4.999 131.950
0.167 9.997 110.682
0.333 19.995 83.376
0.500 29.992 67.784
1.612 96.718 35.062
3.224 193.436 17.475
4.836 290.155 8.738
8.060 483.591 2.184
12.090 725.387 0.386
16.120 967.182 0.068
Weight of rat 275 g
Dose 20 mg/kg
mg
A1 91.23
L
α 4.16 hr −1
µg
B1 69.90
mL
β 0.43 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Human Deoxyribonuclease
Mohler, M., et al., "Altered pharmacokinetics of recominant human deoxyribonuclease in rats due to the
presence of a binding protein", Drug Metabolism and Disposition, Vol. 21, (1993), p. 71 - 75.
Deoxyribonucleases are found in human serum, urine, and a variety of tissues.

These endonucleases catalyze the hydrolysis of DNA to oligonucleotides. It has been
suggested that increased levels of serum deoxyribonucleases may predict
malignancies. Graph the data and find A1, α, B1, β. Check your answers with the
0.000 0.000 24147.000
0.008 0.483 22848.865
0.040 2.415 18463.873
0.081 4.830 14432.548
0.161 9.661 9532.230
0.242 14.491 7039.766
3.027 181.611 2448.500
6.054 363.221 1224.250
9.081 544.832 612.125
15.134 908.053 153.031
22.701 1362.080 27.052
30.268 1816.106 4.782
Patient weight 260 g
Dose 1 mg/kg IV bolus
mg
A1 19250
L
α 8.61 hr −1
ng
B1 4897
mL
β 0.229 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Human Granulocyte Colony-Stimulating Factor
Tanaka, H., and Kaneko, T., "Pharmacokinetic and pharmacodynamic comparisons between human
granulocyte colony-stimulating factor purified from human bladder carcinoma cell line 5637 culture
medium and recombinant human granulocyte colony-stimulating factor produced in Escherichia coli", The
Journal of Pharmacology and Experimental Therapeutics, Vol. 262, (1992), p. 439 - 444.
Human Granulocye Colony-Stimulating Factor (hG-CSF) is used to stimulate the

proliferation of precursor cells and their subsequent differentiation in the bone marrow.
This article compares the pharmacokinetics of hG-CSF produced by two different
methods. In the first method, the hG-CSF was obtained from human bladder carcinoma
cell line 5637 culture medium. In the second method, the hG-CSF was produced by
Escherichia coli. Graph the data and find A1, α, B1, β. Check your answers with the
0.000 0.000 116.309
0.024 1.440 108.526
0.120 7.200 82.266
0.240 14.400 58.192
0.480 28.800 29.129
0.720 43.200 14.593
1.270 76.200 3.016
2.540 152.400 0.101
3.810 228.600 0.014
6.350 381.000 0.003
9.525 571.500 0.001
Weight of rat 250 g
Dose 10 µg/kg IV
mg
A1 116.21
L
t 12 ( α ) 0.24 hours
ng
B1 99.228
mL
t 12 ( β ) 1.27 hours
1. What is AUCα ?
2. What is AUCβ ?
7. What is α?
8. What is β?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Hydrocortisone
Derendorf, H., et al., "Pharmacokinetics and oral bioavailability of hydrocortisone",
Journal of Clinical Pharmacology, Vol. 31, (1991), p. 473 - 476.
This study looks at both the two-compartment model pharmacokinetics and the
oral bioavailability of hydrocortisone. The following data was approximated from the
graph given in this article. Graph the data and find A1, α, B1, β. Check your answers
answers.
0.000 0.000 869.000
0.005 0.317 839.172
0.026 1.587 737.918
0.053 3.175 643.784
0.106 6.349 526.306
0.159 9.524 462.810
1.558 93.458 219.500
3.115 186.916 109.750
4.673 280.374 54.875
7.788 467.290 13.719
11.682 700.935 2.425
15.576 934.580 0.429
Dose 20 mg IV
mg
A1 430
L
α 13.1 hr −1
µg
B1 439
mL
β 0.445 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Levodopa
Sasahara, K., et al., "Dosage form design for improvement of bioavailability of levodopa II:
Bioavailability of marketed levodopa preparations in dogs and parkinsonian patients" Journal of
Pharmaceutical Sciences, Vol. 69, (1980), p. 261 - 265.
Levodopa is an agent used in the treatment of Parkinson's disease. This study

looks at various dosage forms of levodopa and compares the pharmacokinetic
parameters of each. The following data was approximated from the graph given in this
article. Graph the data and find A1, α, B1, β. Check your answers with the answers
given below and answer the remaining questions using the correct answers.
0.000 0.000 11.600
0.005 0.313 11.004
0.026 1.563 8.985
0.052 3.127 7.114
0.104 6.254 4.795
0.156 9.381 3.564
0.608 36.481 1.488
1.216 72.963 0.743
1.824 109.444 0.371
3.040 182.407 0.093
4.560 273.611 0.016
6.080 364.814 0.003
Dose 50 mg IV
mg
A1 8.63
L
α 13.3 hr −1
µg
B1 2.97
mL
β 1.14 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Meropenem
Chimata, M., et al., "Pharmacokinetics of meropenem in patients with various degrees of renal
function, including patients with end-stage renal disease", Antimicrobial Agents and
Chemotherapy, Vol. 37, (1993), p. 229 - 233.
Meropenem is a carapenem antibiotic which has a broad spectrum of activity. It

is used in the treatment of infections caused by both Gram-positive and Gam-negative
bacteria and is active against Enterobacteriaceae and Pseudomonas aeruginosa.
Meropenem is 60% renally and 40% hepatically eliminated. Answer the remaining
questions using the analysis given.
0.000 0.000 41.000
0.037 2.248 39.220
0.187 11.240 33.051
0.375 22.480 27.065
0.749 44.961 18.969
1.124 67.441 13.988
1.378 82.682 11.641
2.756 165.363 5.128
4.134 248.045 2.510
6.890 413.408 0.625
10.335 620.112 0.110
13.780 826.816 0.020
Dose 500 mg IV infusion over 40
minutes
mg
A1 21
L
α 1.85 hr −1
µg
B1 20
mL
β 0.503 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
N-Methylpyridinium-2-Carbaldoxime Chloride
Bodor, N., and Brewster, M., "Problems of delivery of drus to the brain", International
Encyclopedia of Pharmacology and Therapeutics, Vol. 120, (1975)
N-methylpyridinium-2-cabaldoxime chloride (2-PAM) is the drug of choice for the

treatment of orgaonphosphate poisoning. It is mostly renally excreted. This article
considers the fact that this agent is highly hydrophilic and thus has difficulty reaching
the brain. The following data was approximated from the graph given in this article.
Graph the data and find A1, α, B1, β. Check your answers with the answers given
below and answer the remaining questions using the correct answers.
0.000 0.000 41.339
0.060 3.59 23.256
0.120 7.179 14.170
0.179 10.769 9.584
0.241 14.443 7.210
0.299 17.948 6.038
0.449 26.922 4.906
0.598 35.896 4.544
1.204 72.213 3.787
2.407 144.426 2.678
Weight of dog 40 kg
Dose 7.0 mg/kg
mg
A1 5.356
L
α 0.28796 hr −1
mg
B1 35.983
L
β 11.586 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Pyrazine Diazohydroxide
Vogelzang, N., et al., "Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine
diazohydroxide (NSC 361456)", Journal of Cancer Research , Vol. 54, (1994), p. 114 - 119.
Pyrazine diabhohydroxide is an agent which forms a reactive pyrazine dizonium

ion in vivo which acts to destroy tumor cells. This study looks at the pharmacokinetic
parameters of this agent in advanced cancer patients whose cancer was not curable by
any other type of therapy. They were given a dose of 18 mg/m2/day for 5 days every 4
weeks. Most of the following data was collected for a 66 year old male subject. The
remaining data was approximated from the graph given in this article. Graph the data
and find A1, α, B1, β. Check your answers with the answers given below and answer
the remaining questions using the correct answers.
0.000 0.000 9249.000
0.006 0.355 8698.260
0.030 1.777 6834.448
0.059 3.555 5113.957
0.118 7.109 3003.703
0.178 10.664 1909.575
0.450 26.971 634.920
0.899 53.941 296.718
1.349 80.912 148.251
2.248 134.854 37.063
3.371 202.280 6.552
4.495 269.707 1.158
Patient Body Surface 1.82 m2
Area
Dose 18 mg/ m2
µg
A1 8063
mL
α 0.195 min −1
µg
B1 1186
mL
β 0.0257 min −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Rhizoxin
Graham, M., et al., "Preclinical and phase I studie with rhizoxin to apply a pharmacokinetically
guided dose-escalation scheme", Journal of the National Cancer Institute, (1991), p. 494 - 499.
Rhizoxin is a lactone which was obtained from the fungus, Rhizopus chinensis. It
has anti-tumor activity against a broad spectrum of tumor types including LOX
melanoma, A549 lung tumors, and MX-1 mammary tumors. This study looks at dosing
of rhizoxin. Patients with nontreatable tumors who had a life expectancy of more than
12 weeks were given doses of 12 mg/ m2. The following data was approximated from
the graph given in this article. Graph the data and find A1, α, B1, β. Check your
correct answers.
Time(hr)Time(min) Cp(µMol/mL)
0.000 0.000 1.670
0.017 1.040 1.566
0.087 5.199 1.215
0.173 10.397 0.893
0.347 20.794 0.503
0.520 31.192 0.307
5.975 358.524 0.060
11.951 717.049 0.030
17.926 1075.573 0.015
29.877 1792.622 0.004
44.816 2688.933 0.001
Patient Body Surface 1.82 m2
Area
Dose 12 mg/ m2
µM
A1 1.55
mL
α 4.00 hr −1
µM
B1 0.12
mL
β 0.116 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Terbinafene
Kovarik, J., et al., "Dose-proportional pharmacokinetics of terbinafine and its N-demethylated
metabolite in healthy volunteers", British Hournal of Dermatology, Vol. 126, (1992), p. 8 - 13.
Terbinafene is an antifungal agent which acts by interfering with ergosterol

biosynthesis. It is active against Trichophyton, Epidermophyton, and Microsporum.
Approximately 70% of an oral dose is absorbed. Terbinafene has an N-demethylated
metabolite which is active. The following data was approximated from the graph given
in this article. Graph the data and find A1, α, B1, β. Check your answers with the
0.000 0.000 2.500
0.136 8.139 2.339
0.678 40.694 1.796
1.356 81.387 1.298
2.713 162.774 0.696
4.069 244.161 0.393
31.223 1873.371 0.051
62.446 3746.742 0.026
93.669 5620.112 0.013
156.114 9366.854 0.003
Dose 750 mg
ng
A1 2398
mL
α 0.511 hr −1
ng
B1 102
mL
β 0.0222 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Verrucarol
Barel, S., Yagen, B., and Bailer, M., "Pharmacokinetics of the trichothecen mycotoxin verrucarol
in dogs", Journal of Pharmacetuical Seciences, Vol. 79, (1990), p. 548 - 550.
Verrucarol is a toxin which is related to toxins which have anti-tumor activity.

This study looks at the pharmacokinetics of verrucarol in dogs. The following data was
approximated from the graph given in this article. Graph the data and find A1, α, B1, β.
Check your answers with the answers given below and answer the remaining questions
using the correct answers.
0.000 0.000 0.667
0.028 1.670 0.650
0.139 8.351 0.589
0.278 16.702 0.525
0.557 33.405 0.426
0.835 50.107 0.352
1.221 73.271 0.276
2.442 146.543 0.135
3.664 219.814 0.068
6.106 366.357 0.017
9.159 549.535 0.003
Weight of Dog 22.5 kg
Dose 0.4 mg/ kg
ng
A1 126.05
mL
α 0.0415 min −1
ng
B1 540.58
mL
β 0.00946 min −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Answers
Aspirin Caffeine Ceftazidime Cocaine

1. 8.019 µg ⋅min 1. 2.15 µg ⋅ h 1. 22.87 mg ⋅ h 1. 3239.2 ng ⋅ min
mL mL L mL
2. 36.2 µg ⋅ min 2. 39.57 µg ⋅ h 2. 118.78 mg ⋅ h 2. 10266.7 ng ⋅ min
mL mL L mL
3. 31.1 mL 3. 41.72 µg ⋅ h 3. 141.65 mg ⋅ h 3. 13505.89
min mL L ng ⋅ min
mL
4. 2.62 minutes 4. 7.67 L 4. 7.0598 L 4. 44.43 mL
h h min
5. 155.48 mL 5. 33.35 L 5. 14.41 L 5. 987.2 mL
6. 86.92 mL 6. 16.28 L 6. 4.06 L 6. 367.1 mL
7. 81.57 mL 7. 0.141 hours 7. 0.0843 hours 7. 1.91 minutes
8. 0.648 min 8. 3.014 hours 8. 1.415 hours 8. 15.4 minutes
9. 3.47 min 9. 2.39 h-1 9. 2.32 h-1 9. 0.1346 min-1
10. 0.598 min-1 10. 0.471 h-1 10. 1.738 h-1 10. 0.1210 min-1
11. 0.358min-1 11. 2.266 h-1 11. 4.65 h-1 11. 0.1514 min-1
12. 0.314min-1 12. 19.65 µg 12. 246.2 mg 12. 1634.6 ng
mL L mL
13. 15.82 µg 13. 0.655 hours 13. 0.365 hours 13. 8.35 minutes
mL
14. 1.928 minutes 14. 51.2% 14. 39.2% 14. 59.2%
15. 44.1% 15. Yes 15. Yes 15. No
16. Yes
17. 0.381 min-1

Buprenorphine Cefazolin Clentiazem 1,2-Diethyl-3-hydroxpyridine-4-
one
1. 10.54 ng ⋅ h 1. 42.73 µg ⋅ h 1. 13.9 ng ⋅ h 1. 15.22 mg ⋅ h

mL mL mL L
2. 36.9 ng ⋅ h 2. 214.59 µg ⋅ h 2. 207.3 ng ⋅ h 2. 21.39 mg ⋅ h
mL mL mL L
3. 47.4 ng ⋅ h 3. 257.32 µg ⋅ h 3. 221.2 ng ⋅ h 3. 36.62 mg ⋅ h
mL mL mL L
4. 366.8 mL 4. 3.89 L 4. 90.4 L 4. 375.5 mL
h h h h
5. 2.85 hours 5. 6.78 L 5. 1159.2 L 5. 988.2 mL
6. 1.35 L 6. 3.035 L 6. 372.5 L 6. 352.3 mL
7. 0.34 L 7. 0.143 hours 7. 0.257 hours 7. 0.341 hours
8. 0.178 hours 8. 1.21 hours 8. 8.89 hours 8. 1.824 hours
9. 2.58 hours 9. 2.163 h-1 9. 0.868 h-1 9. 0.724 h-1
10. 0.981 h-1 10. 1.28 h-1 10. 0.243 h-1 10. 1.066 h-1
11. 1.075 h-1 11. 1.96 h-1 11. 1.67 h-1 11. 0.62 h-1
12. 2.11 h-1 12. 329.44 µg 12. 53.69 ng 12. 39.03 mg
mL mL L
13. 51 ng 13. 0.50 hours 13. 1.35 hours 13. 1.016 hours
mL
14. 0.736 hours 14. 55.2% 14. 47.4% 14. 55.4%
15. No
15. 74.9% 15. Yes 15. Yes
16. No
17. Can't be calc
2,2-dimethylaziridine Furosemide Human Hydrocortisone
Deoxyribonuclease
1. 102.7 µg ⋅ min 1. 0.304 mg ⋅ h 1. 2235.78 ng ⋅ h 1. 32.8 mg ⋅ h
mL L mL L
2. 89.47 µg ⋅ min 2. 0.802 mg ⋅ h 2. 21384.3 ng ⋅ h 2. 986.5 mg ⋅ h
mL L mL L
3. 192.16 µg ⋅ min 3. 1.106 mg ⋅ h 3. 23620.1 ng ⋅ h 3. 1019.3 mg ⋅ h
mL L mL L
4. 1498.7 mL 4. 19.88 L 4. 11.01 mL 4. 19.62 mL
min h h h
5. 15.78 L 5. 20.71 L 5. 48.07 mL 5. 44.1 mL
6. 5.7 L 6. 7.67 L 6. 10.77 mL 6. 23.01 mL
7. 1.695 minutes 7. 0.1005 hours 7. 0.0805 hours 7. 0.053 hours
9. 0.148 min-1 9. 2.55 h-1 9. 1.929 h-1 9. 6.838 h-1

10. 0.263 min-1 10. 2.59 h-1 10. 1.0223 h-1 10. 0.853 h-1
11. 0.093 min-1 11. 2.71 h-1 11. 5.89 h-1 11. 5.85 h-1
12. 50.5 µg 12. 2.87 mg 12. 24147 ng 12. 869 mg
mL L mL L
14. 56.5% 14. 62.99% 14. 28.9% 14. 47.8%
15. No 15. No 15. Yes 15. Yes
Flurbiprofen Glycyrrhizin Human Granulocyte Levodopa

Colony-Stimulating
Factor
1. 20.82 mg ⋅ h 1. 21.93 mg ⋅ h 1. 40.24 ng ⋅ h 1. 0.649 mg ⋅ h
L L mL L
2. 329.6 mg ⋅ h 2. 162.56 mg ⋅ h 2. 181.81 ng ⋅ h 2. 2.61 mg ⋅ h
L L mL L
3. 350.42 mg ⋅ h 3. 184.5 mg ⋅ h 3. 222.05 ng ⋅ h 3. 3.25 mg ⋅ h
L L mL L
4. 7.42 mL 4. 29.8 mL 4. 11.26 mL 4. 15.37 L
h h h h
5. 42.4 mL 5. 69.33 mL 5. 20.62 mL 5. 13.48 L
6. 24.5 mL 6. 34.13 mL 6. 11.6 mL 6. 4.31 L
7. 0.297 hours 7. 0.167 hours 7. 2.89 h-1 7. 0.052 hours
8. 3.96 hours 8. 1.61 hours 8. 0.546 h-1 8. 0.61 hours
9. 1.35 h-1 9. 2.048 h-1 9. 1.625 h-1 9. 4.25 h-1

10. 0.303 h-1 10. 0.873 h-1 10. 0.971 h-1 10. 3.56 h-1
11. 0.856 h-1 11. 1.67 h-1 11. 0.839 h-1 11. 6.62 h-1
12. 106.18 mg 12. 161.13 mg 12. 215.44 ng 12. 11.6 mg
L L mL L
13. 1.2 hours 13. 0.61 hours 13. 0.711 hours 13. hours
14. 42.2% 14. 50.8% 14. 43.8% 14. 68.0%
15. Yes 15. Yes 15. Yes 15. Yes
Meropenem Pyrazine Diazohydroxide Verrucarol
1. 11.35 mg ⋅ h 1. 41348.7 1. 3037.35 ng ⋅ min
L µg ⋅ min mL
mL
2. 39.76 mg ⋅ h 2. 46147.9 2. 57143.8
L µg ⋅ min ng ⋅ min
mL mL
3. 51.11 mg ⋅ h 3. 87496.6 3. 60181.1 ng ⋅ min
L µg ⋅ min mL
mL
4. 9.78 L 4. 0.3744 mL 4. 149.5 mL
h min min
5. 19.45 L 5. 14.57 mL 5. 15.81 L
6. 12.20 L 6. 3.542 mL 6. 13.5 L
7. 0.375 hours 7. 3.55 minutes 7. 16.7 minutes
9. 1.16 h-1 9. 0.0474 min-1 9. 0.0155 min-1

10. 0.802 h-1 10. 0.106 min-1 10. 0.0253 min-1
11. 0.391 h-1 11. 0.0676 min-1 11. 0.0101 min-1
12. 41 mg 12. 9249 µg 12. 666.63 ng
L mL mL
14. 37.3% 14. 75.7% 14. 28.1%
15. No 15. No 15. Yes
N-methylpyridinium-2- Terbinafene
carbaldoxime chloride
1. 18.6 mg ⋅ h 1. 4692.8 ng ⋅ h
L mL
2. 3.106 mg ⋅ h 2. 4594.6 ng ⋅ h
L mL
3. 21.71 mg ⋅ h 3. 9287.4 ng ⋅ h
L mL
4. 12.9 L 4. 80.75 L
h h
5. 1.11 L 5. 3637.6 L
6. 6.77 L 6. 300 L
7. 2.41 hours 7. 1.36 h
8. 0.0598 hours 8. 31.2 h
9. 1.752 h-1 9. 0.0421 h-1

10. 1.905 h-1 10. 0.2692 h-1
11. 8.218 h-1 11. 0.222 h-1
12. 41.339 mg 12. 2500 ng
L mL
13. 0.327hours 13. 6.42 hours
?14. 45.5% 14. 91.8%
15. Yes 15. No

BASIC PHARMACOKINETICS - CHAPTER 11: Multicompartment Model

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`PHARMACOKINETICS: MAMMILLARY MODELS

• Compartment Two (X2, the peripheral compartment) cannot normally be sampled. It

• The Body is the sum of both compartments.

1. Intravenous Bolus Administration: Plasma Concentration Data

Plasma Concentration vs. Time

Plasma Concentration vs. Time

On semilogarithmic paper (logarithm on the Y axis), the terminal phase is linear,

For a two-compartment open model, The plasma concentration follows the

i.e., the concentration of drug in the plasma declines bi-exponentially with

i. A1 and B1 are intercept constants (m/L3)

2.3 Obtaining Pharmacokinetic Parameters by “Feathering”

d. Draw a straight line through the linear terminal elimination phase

i. Measure the intercept of the “feathered” line; it will be equal to A1

When t is large, e-αt < e-βt. Hence, Eq (11.1.2) becomes

k12 = α + β − k10 − k21 = (11.1.19)

2.6 Dosage Regimens

All dosage regimen equations strictly apply only when,

When t is large, e-αt < e-βt. Hence, Eq. (11.1.29) becomes,

This is compared to the mass modification of Eq.(11.1.14),

The equations become complex and it is therefore difficult to obtain useful

4.1 Intravenous Infusion

The plasma concentrations at first rise faster than an open one-

Where α is as before in equation (11.1.3)

If theer infusion was terminated at time T, the concentration at time T

4.2 Oral Administration

Cp = A1e −α t + B1e − β t + C1e −γ t (11.1.36)

Metzler, C.M., Usefulness of the two-compartment open model in pharmacokinetics, J. Amer.

Gillette, J.R., The importance of tissue distribution in pharmacokinetics, J. Pharmacokin.

It may be calculated after an intervenous dose by:

It may be calculated after an intervenous infusion by

3. Relationships between apparent volumes:

However, systemic clearance is calculated by:

Comparing Eqs (11.2.3) and (11.2.7) we find:

c. First order absorption

d. Dissolution and absorption (Type 1)

e. Dissolution and absorption (Type 2)

3. Disposition Function for Compartment One

a. Using the disposition function:

ki is a composite rate constant. Thus for the:

c. The “Hidden Hand” Method

5. LaPlace Transfom for peripheral compartments

6. Method if the denominator contains the factor s2.

Aspirin is an analgesic/ antipyretic commonly used to relieve minor pain and is

Buprenorphine is a morphine derivative which has twice the duration of action

Time(hr) Time(min) Cp(mg/L)

This study looks at the cardiovascular effects of caffeine. Caffeine is known to

Time(hr) Time(min) Cp(mg/L)

Cefazolin is a cephalosporin antibiotic used in the treatment of many types of

Time(hr) Time(min) Cp(mg/L)

Ceftazidime is a cephalosporin antibiotic. This study explores the effect of

Two-Chloro-2-deoxyadenosine is an antitumor agent used in the treatment of

Clentiazem is an derivative of diltiazem which is under investigation for its use in

1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) is an iron chelator which is orally

Flurbiprofen is an anti-inflammatory and analgesic agent. This study compares

Glycyrrhizin is a component of licorice which is proposed to have anti-

Deoxyribonucleases are found in human serum, urine, and a variety of tissues.

Human Granulocye Colony-Stimulating Factor (hG-CSF) is used to stimulate the

Levodopa is an agent used in the treatment of Parkinson's disease. This study

Meropenem is a carapenem antibiotic which has a broad spectrum of activity. It

N-methylpyridinium-2-cabaldoxime chloride (2-PAM) is the drug of choice for the

Pyrazine diabhohydroxide is an agent which forms a reactive pyrazine dizonium

Terbinafene is an antifungal agent which acts by interfering with ergosterol