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Extravascular

administration: monitoring
drug in urine
Methods to compute
PK parameters from urinary data
1. the ‘‘amount remaining to be excreted’’
method (ARE); also known as the sigma-
minus method

2. The rate of excretion method


Sigma-Minus Method
Amount of unchanged or excreted drug in urine (Xu) 
is given by:
KrKaFXo  1 e  Kt Ke Kat 
Xu     
K  Ka K  Ka ( K  Ka) 
the cumulative amount of drug excreted in the urine at
t = ∞ is:  K FX
Xu  r 0
K
Substitution for X u and rearrangement yields:

X u

X  Xu 
u
Ka  K

Ka  e  Kt  K  e  Kat 
Sigma-Minus Method
 Generally, when Ka>>K, at certain time point the
absorption process ends (become negligible) as we
referred earlier by the terminal phase. Previous Eqn.
become: 
X u  Xu 
X u
Ka  K
 
Ka  e  Kt

 Taking the logarithm, we get:


 

 
 
log X u  Xu  log 
X u Ka

 
Kt
 Ka  K  2.303
  
Thus the plot of log X u  Xu vs. end of the time
interval gives a line with a slope equal to –K/2.303
Sigma-Minus Method: Example
 An oral tablet with a strength of 500 mg of a
drug was administered. The drug is one that
is partially eliminated by urinary excretion of
unchanged drug following one-compartment
model distribution and first-order elimination.

 Using the urinary data presented in the


following table, calculate elimination rate
constant
Sigma-Minus Method: Example

Time Volume Concentration


interval (hr) (ml) (mg/ml)

0-2 50 1.272
2-4 25 2.972
4-8 100 0.915
8-16 200 0.280
16-24 150 0.075
24-32 200 0.011
Sigma-Minus Method:
1- Calculate cumulative amount of drug
eliminated

Cumulative
Time Volume Concentration Amount
Amount
interval (hr) (ml) (mg/ml) (mg)
(mg)
0-2 50 1.272 63.60 63.6
2-4 25 2.972 74.30 137.9
4-8 100 0.915 91.50 229.4
8-16 200 0.280 56.00 285.4
16-24 150 0.075 11.25 296.7
24-32 200 0.011 2.20 298.9
Sigma-Minus Method:
2- Calculate amount remaining to be excreted
(ARE)

ARE
Xu   Xu 
Cumulative
Time Amount
Amount
interval (hr) (mg)
(mg) (mg)
0-2 63.60 63.6 235.3
2-4 74.30 137.9 161.0
4-8 91.50 229.4 69.5
8-16 56.00 285.4 13.5
16-24 11.25 296.7 2.2
24-32 2.20 298.9 0
Sigma-Minus Method:
3- Plot time (end of interval) vs. log(ARE)

ARE
Xu 
2.5
Time 
 Xu
(hr) Terminal phase
(mg) 2
(straight line)
2 235.3
log(ARE)

1.5
4 161.0
8 69.5 1

16 13.5 0.5

24 2.2
0
32 0 0 5 10 15 20 25 30
time (endpoint of the interval, hr)
Sigma-Minus Method:
4- draw the best fit line to the linear portion of the
curve (terminal phase)
2.5

y = -0.0937x + 2.6045
log(ARE)

1.5
R2 = 0.9991

0.5

0
0 5 10 15 20 25 30
time (endpoint of the interval, hr)
Sigma-Minus Method: Example
 The plot of log(ARE) vs. end of the time
interval point of urine collection time gives a
line with a slope equal to –K/2.303

K   slope  2.303
1
K  0.0937  2.303  0.22 hr
The rate of excretion method
Xu
 Kr  X
t
substituting the value of X from previous lecture (oral
equation), we get:

t

Xu K r KaFXo  Kt  Kat

( Ka  K )
e e 
Generally, when Ka>>K, at certain time point the
absorption process ends (become negligible) as we
referred earlier by the terminal phase. Previous Eqn.
become:
Xu K r KaFXo  Kt
t

( Ka  K )
e  
The rate of excretion method
Taking the logarithm, we get:
 Xu   K r KaFXo  Kt
log    log   
 t   ( Ka  K )  2.303
Thus the plot of dXu/dt vs. mid point of urine
collection time gives a line with a slope equal
to –K/2.303

The total amount to be eliminated ( X u ) is:


K r FX 0
X u
K
The rate of excretion method:
Example
 An oral tablet with a strength of 500 mg of a
drug was administered. The drug is one that
is partially eliminated by urinary excretion of
unchanged drug following one-compartment
model distribution and first-order elimination.

 Using the urinary data presented in the


following table, calculate elimination rate
constant
The rate of excretion method:
Example

Time Volume Concentration


interval (hr) (ml) (mg/ml)

0-2 50 1.272
2-4 25 2.972
4-8 100 0.915
8-16 200 0.280
16-24 150 0.075
24-32 200 0.011
The rate method:
1- Calculate amount of drug eliminated

Time Volume Concentration Amount


interval (hr) (ml) (mg/ml) (mg)

0-2 50 1.272 63.60


2-4 25 2.972 74.30
4-8 100 0.915 91.50
8-16 200 0.280 56.00
16-24 150 0.075 11.25
24-32 200 0.011 2.20
The rate method:
2- Calculate the change in time

Time Volume Concentration Amount Δt


interval (hr) (ml) (mg/ml) (mg) (hr)

0-2 50 1.272 63.60 2


2-4 25 2.972 74.30 2
4-8 100 0.915 91.50 4
8-16 200 0.280 56.00 8
16-24 150 0.075 11.25 8
24-32 200 0.011 2.20 8
The rate method:
3- Calculate the rate of urinary excretion

 Xu 
Time Volume Concentration Amount Δt  
interval (hr) (ml) (mg/ml) (mg)  t 
(hr)
mg/hr
0-2 50 1.272 63.60 2 31.80
2-4 25 2.972 74.30 2 37.15
4-8 100 0.915 91.50 4 22.88
8-16 200 0.280 56.00 8 7.00
16-24 150 0.075 11.25 8 1.41
24-32 200 0.011 2.20 8 0.28
The rate method:
4- Plot time (mid of interval) vs. log(dXu/dt)
2

 Xu 
Time   Terminal phase
 t  1.5
(h) (straight line)
mg/hr
1
31.80
log (dXu/dt)

1
3 37.15 0.5

6 22.88
0
0 5 10 15 20 25 30
12 7.00
-0.5
20 1.41
28 0.28 -1
time (midpoint of the interval, hr)
The rate method:
5- draw the best fit line to the linear portion of
the curve (terminal phase)
2

1.5
y = -0.0874x + 1.8946
R2 = 1
1
log (dXu/dt)

0.5

0
0 5 10 15 20 25 30

-0.5

-1
time (midpoint of the interval, hr)
The rate of excretion method:
Example
 The plot of dXu/dt vs. mid point of urine
collection time gives a line with a slope equal
to –K/2.303

K   slope  2.303
1
K  0.0874  2.303  0.2 hr

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