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- Introduction Pharmacoeconomic
- _BASIC PHARMACOKINETICS - CHAPTER 7: Oral Dosing
- BASIC PHARMACOKINETICS - CHAPTER 5: IV Infusion
- Problems for Zero-Order Kinetics and First-Order Kinetics
- Compartment Models
- Multiple Dosage Regimen
- BP
- BASIC PHARMACOKINETICS - CHAPTER 13: Non-linear kinetics
- Pharmacokinetics
- Kinetics of Drugs
- BASIC PHARMACOKINETICS - CHAPTER 3: Pharmacological Response
- Looriegelman and Comp. Application in biopharmaceutics
- Clinical Pharmacokinetics Sample Chapter
- BASIC PHARMACOKINETICS-Ch2: Mathematics Review
- BASIC PHARMACOKINETICS - PTER 4: IV Bolus
- BASIC PHARMACOKINETICS - CHAPTER 6: Biopharmaceutical factors
- BASIC PHARMACOKINETICS - CHAPTER 8: Bioavailability
- BASIC PHARMACOKINETICS - CHAPTER 10: Dosage
- BASIC PHARMACOKINETICS - CHAPTER 14: Exams I
- BASIC PHARMACOKINETICS - CHAPTER 14: Exams I

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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.

may consist of organs or tissues which, being poorly perfused with blood, are in slow

equilibrium distribution with the blood.

Recall that for a one-compartment open model, the plasma concentration follows the

equation:

Cp = Cp0 e( − kT ) (11.1.1)

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)

1000

Alpha Phase

Plasma Concentration

Beta Phase

100

10

0 5 10 15 20 25 30

Time

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.

equation:

Cp = A1e( ) + B1e( )

−α T − βT

(11.1.2)

time.

2.1 Symbols

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)

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

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

(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?)

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

(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.

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.

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.

k Dose ( − β T )

X 2 = 12

α −β

e ( ) (11.1.30)

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

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.

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

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

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

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.

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).

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).

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.

Dose Dose

V1 = = (11.2.1)

K ( AUC )

∞

C p0

0

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

∞

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)

Dose

Cls = (11.2.7)

( AUC )0

∞

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

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.

kr ka FD

( in ) = (11.3.5)

( s + kr )( s + ka )

Where: kr is the first order dissolution rate constant

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.

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.

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

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.

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.

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.

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.

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.

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 ?

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?

Caffeine

Shi, J., et al., "Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor

effects", Clinical Pharmacology and Therapeutics, Vol. 53, (1993), p. 6 - 14.

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 ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

Cefazolin

Nightingale, C., et al., "Changes in pharmacokinetics of cefazolin due to

stress", Journal of Pharmaceutical Sciences, Vol. 64, (1975), p. 712 - 714.

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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.

Patient weight 65 kg

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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.

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

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

Patient weight 77 kg

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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

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 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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

Glycyrrhizin

Tsai, T., et al., "Pharmacokinetics of glycyrrhyzin after intravenous administration to rats",

Journal of Pharmaceutical Sceinces, Vol. 81, (1992), p. 961- 963.

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

with the answers given below and answer the remaining questions using the correct

answers.

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

0.000 0.000 161.130

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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

answers given below and answer the remaining questions using the correct answers.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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

answers given below and answer the remaining questions using the correct answers.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

7. What is α?

8. What is β?

9. What is k21 ?

10. What is k10 ?

11. What is k12 ?

12. What is your patient's Vd ss ?

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?

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

with the answers given below and answer the remaining questions using the correct

answers.

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

0.000 0.000 869.000

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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)

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.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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

answers with the answers given below and answer the remaining questions using the

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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

answers given below and answer the remaining questions using the correct answers.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

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.

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.

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

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 ?

3. What is AUCtotal ?

4. What is your patient's clearance?

5. What is your patient's Vβ ?

6. What is your patient's V1?

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 ?

12. What is your patient's Vd ss ?

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?

Answers

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

Buprenorphine Cefazolin Clentiazem 1,2-Diethyl-3-hydroxpyridine-4-

one

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

8. 7.296 minutes 8. 0.722 hours 8. 3.027 hours 8. 1.56 hours

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

13. 4.65 minutes 13. 0.322 hours 13. 0.433 hours 13. 0.267 hours

14. 56.5% 14. 62.99% 14. 28.9% 14. 47.8%

15. No 15. No 15. Yes 15. Yes

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

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

8. 1.378 hours 8. 26.97 minutes 8. 73.3 minutes

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

13. 0.967 hours 13. 11.97 minutes 13. 46.15 minutes

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

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

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