Biopharmaceutics and

pharmacokinetics
course code(PT809)
Lecture 4
By
Dr/Aliaa Ismail Adly
Lecturer of Pharmaceutics
 Calculation of
elimination rate constant(k)
based on urinary excretion data

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 To use the urine data , a fraction of drug must be
excreted unchanged at least 20%.
 Urine data is a mirror image of plasma data
especially for drugs which are excreted
unchanged in urine.
Assuming renal clearance is constant, Du/t is
proportional to plasma drug conc.

Plotting Du/t versus t* is like plotting Cp versus

time.
 The measured urinary excretion rate reflects
the average plasma concentration during the
collection interval.
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1-Urinary excretion rate
method

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 In this method the excretion rate of the
drug is assumed to be first order.
d Du / dt = ke DB
where, DB=Amount of drug in the body
Du = Amount of drug excreted in
the urine
ke= excretion rate constant
 Because DB= DB0e –kt,
then dDu / dt = keDB0e -kt
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 The logarithmic form of this equation yields;

dDu kt 
log dtlog ke DB 


dt 2.303
K= the total elimination rate constant
Ke= the renal excretion rate constant
DB= the initial amount of drug in the body
Du = the amount of drug excreted unchanged in
urine
t* = the mid point time
Difference between t and t*
 t is the time interval for
collection of urine sample.

 t* is the midpoint of collection

period.
 Why t* ?
 Because the drug urinary excretion rate
(dDu/dt) cannot be determined
experimentally at any given instant.
 In practice, urine is collected over a
specified time interval, and the urine
specimen is analyzed for drug.
 An average urinary excretion rate is then
calculated for that collection period.
 The average dDu/dt is then plotted against
the average time (t*).
Note:

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 Plotting on a Semilog Paper
Plot dDu/dt versus midpoint time (t*)

ept
int erc
keDB

Slope= - k/2.303
dDu / dt

mid point time (t*)

• Note that the slope is a function of the
elimination rate constant k and not of the
urinary excretion rate constant ke.

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• In case of rapid iv injection
O
DB = the dose ,
O
therefore if DB is known the renal excretion
rate constant can be obtained as
Ke= intercept / Dose
• Because both k and ke can be calculated by
this method, the non renal Knr constant for any
route of elimination other than renal excretion
can be calculated as
Knr =K-Ke

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Example:
A single IV dose of an antibiotic was given
to a 50-kg woman at a dose level of 20
mg/kg. Urine and blood samples were
removed periodically and assayed for
parent drug. The following data were
obtained:

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14
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Example
Time Du (mg) Du/t Du/t t* (hr)
mg/hr
0.25 160 160/0.25 640 0.125

0.5 140 140/0.25 560 0.375

1.0 200 200/0.5 400 0.750

2.0 250 250/1 250 1.50

4.0 188 188/2 94 3.0

6.0 46 46/2 23 5.0

 Note
• A similar graph of the Cp values versus t
should yield a curve with a slope having
the same value as that derived from the
previous curve.
• Note that this method uses the time of
plasma sample collection, not the midpoint
of collection.

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 2-Sigma-Minus Method
 Also called the Amount of Drug Remaining
to be Excreted Method (ARM).
 It is an alternative method for the calculation
of k from urinary excretion data.
Sigma-Minus Method

Du - Du = Du e-kt

log (Du - Du) = log Du - kt /2.303

•Du is the cumulative amount of drug that is

ultimately excreted unchanged in urine.
•Du is the cumulative amount of drug excreted
unchanged in urine after time (t).
•(Du - Du) is the amount of drug remaining to
be excreted after time(t).
Time Money Cumulative Money
(t) Spending money Remaining
at time (t) spending at time(t)
at time (t)

1 40 40 60

2 30 70 30

3 20 90 10

4 10 100 0

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Example
Use these data to calculate k
Time Du Du Du - Du
(hr) (mg) (cumulative)
0.25 160 160 984-160=824
0.5 140 300 984-300=684
1.0 200 500 984-500=484
2.0 250 750 984-750=234
4.0 188 938 984-938=46
6.0 46 984 984-984= 0
Sigma-Minus Plot
On a semilog paper:
Intercept
D u

Du- Du

Slope= -k/2.303

Time
 Unchanged in urine (fe):

Du = (ke/k )( absorbed Dose)

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 calculation of ke
from Sigma-Minus Plot
On a semilog paper:
Du∞ = (fe * dose)
D u

Du- Du = (ke*dose)/k

Slope= -k/2.303

Time
 Sigma-Minus Method versus
plasma data method

NOTE: compare

Cp= Cpo e-kt

Du - Du = Du e-kt

 Comparison of the Rate and
the Sigma-Minus Methods
• The sigma-minus method requires knowing the Du∞
and even a single missed urine collection will
invalidate the entire study.
• This method also requires the collection of urine
until urinary drug excretion is complete;
prematurely ending the study early will invalidate
the study.
• Any sample error in the assessment of Du∞
introduces an error in curve fitting.

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Problems in Obtaining Valid
Urinary Excretion Data

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Certain factors can make it difficult to obtain
valid urinary excretion data. Some of these
factors are as follows:
1- A significant fraction of the unchanged
drug must be excreted in the urine (at least
20%).

2- The assay technique must be specific for

the unchanged drug and must not include
interference due to drug metabolites that
have similar chemical structures.

3- Frequent sampling is necessary for a

good curve description. 28
4- Urine samples should be collected
periodically until almost the entire drug is
excreted. In practice, approximately seven
elimination half-lives are needed for 99% of
the drug to be eliminated.

5-Variations in urinary pH and volume may

cause significant variation in urinary
excretion rates.

6-Subjects should be carefully instructed as

to the necessity of giving a complete urine
specimen (i.e, completely emptying the
bladder). 29