Pharmacokinetics

Lecture 10

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Determination of Pharmacokinetic
parameters from urine data

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 Determination of Pharmacokinetic parameters from
urine data
IV bolus administration / Monitoring drug in urine

▪ Urine collection is a non invasive technique for sample collection

▪ It allows direct measurement of bioavailability either absolute or relative
▪ To compute pharmacokinetic parameters from urinary excretion data we
use one of two methods:
a) Rate of excretion method
b) Sigma minus method (amount remaining to be excreted method ARE)

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 Determination of Pharmacokinetic parameters from urine
data

a) Rate of excretion method

• k (elimination rate constant) can be calculated from urinary excretion data.

• The excretion rate of the drug is assumed to be first order.
• Ku is the renal excretion rate constant.
• Du is the amount of drug excreted unchanged in the urine.

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 Scheme of the Model
For a single i.v. dose,

IV Dose ku Du
DB = CpVd
km

dDu/dt = kuDB

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 Rate of Drug Excretion in the Urine
Equations
dDu = kuDB
dt
But DB= DB0e-kelt
dDu
= ku DB e −kel t
dt

dDu Log dDu/dt = log Ku DB0 – Kt/2.303

= ln kuDB − kel t
lnTherefore, Or
dt

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 Plotting on a Semilog Paper
Plot dDu/dt vs. Time

kuDB

dDu/dt
Slope= -k/2.303

Time

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▪ 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*).
▪ t is the time interval for collection of urine sample.
▪ t* is the midpoint of collection period.
▪ Assuming renal clearance is constant, Du/t is proportional to plasma
drug conc, and plotting Du/t vs. t* is like plotting Cp vs. time.
▪ The measured urinary excretion rate reflects the average plasma
concentration during the collection interval.

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Example
Time Du Du/t mg/hr t* (hr)
(hr) (mg)
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
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Example t*= t1+t2/2

Time Amount Rate of Excretion

Midpoint
Interval Excreted dDu/dt
Time t* (hr)
t(hr) Du (mg) (mg/hr)

2 83.3 1 83.3/2=41.65
4 49.2 3 49.2/2= 24.6
6 28.4 5 28.4/2= 14.2
8 16.4 7 16.4/2= 8.2
10 9.7 9 9.7/2= 4.85
12 5.6 11 5.6/2= 2.8
18 6.3 15 6.3/6= 1.05
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 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*).

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 Example
Drug amount in
the urine t
Time Volume Concentration (mg) (Time Du/t
t*
(h) (mL) (mg/mL) Amount = interval) (mg/hr)
volume*conc (hr)

1 200 0.200 40 1 40 0.5

2 50 0.400 ------- ------- ------- -------

3 50 0.200 ------- ------- ------- -------

4 100 0.050 ------- ------- ------- -------

5 25 0.100 ------- ------- ------- -------

6 125 0.010 ------- ------- ------- -------

12 250 0.005 ------- ------- ------- -------

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 b) Sigma-Minus Method

▪ Also called the Amount of Drug Remaining to be Excreted

Method.
▪ It is an alternative method for the calculation of k from
urinary excretion data.
▪ It is more accurate than the rate of excretion method.

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 Sigma-Minus Method
Scheme of the Model
For a single i.v. dose,

IV Dose ku Du
DB = CpVd
km

dDu/dt = kuDB

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 Sigma-Minus Method

By
integration
dDu = kuDB ku D 0
dt Du = (1− e ) −kt

k
Where,
• Du is the cumulative amount of drug excreted
unchanged in the urine until time t
• Ku is renal excretion constant
• K is total elimination rate constant (get from t half)
• Do is the dose
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Sigma-Minus Method (cont)
The amount of drug that is ultimately excreted at time
infinity will be equal to Du
Du = ku/k (D0) (2)
By substituting in the previous equation (1)
Du - Du = Du e-kt (3)
To obtain a linear equation:
Ln (Du - Du) = ln Du - kt (4)
Or Log (Du - Du) = log Du - kt/2.303

Where, (Du - Du) is the amount of drug remaining to

be excreted.
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Sigma-Minus Plot
On a semilog paper:

Du

Du-Du
Slope=
Slope= -k
el
-k/2.303

Time
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Example
Use these data to calculate kel
Time (hr) Du (mg) Du (cum) Du - Du

0.25 160 160 824

0.5 140 300 684
1.0 200 500 484
2.0 250 750 234
4.0 188 938 46
6.0 46 984 0
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 2. Sigma- minus or (ARE)
Time Cumulative Amount
Amount Excreted
Interval Excreted Du∞-Du
Du (mg)
(hr) Du (mg)
2 83.3 83.30 200.17-83.3=116.87

4 49.2 132.50 67.67

6 28.4 160.90 39.27

8 16.4 177.27 22.87

10 9.7 186.97 13.17

12 5.6 192.57 7.57

18 6.3 198.87 1.27

24 1.3 200.17 (Du∞) -----

 Rate excretion and sigma minus method
Time Cp Du Du/t (mg/hr) (t)* (hr) Cum. Du D∞u – Du
(hr) (mg/ml) (mg) mid (mg)
point
0 0 0
0.25 4.2 160 160/0.25 640 0.125 160 824
0.50 3.5 140 140/0.25 560 0.375 300 684
1.00 2.5 200 200/0.5 400 0.75 500 484
2.00 1.25 250 250/1 250 1.5 750 234
4.00 0.31 188 188/2 94 3.00 938 46
6.00 0.08 46 46/2 23 5.00 984 -

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Cumulative Amount of Drug Excreted in the Urine
Plot

Cumulative amount excreted

One needs to
collect urine
Du samples for a
minimum of 7-
10 half-lives of
the drug to
assure all the
drug is excreted
into the urine.

Time
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IV bolus administration
Monitoring drug in urine

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Comparison between the Rate and the Sigma-Minus Method
1- In the rate method, Du need not be known, and the loss of one urine
specimen does not invalidate the entire study.
2- The sigma-minus method needs accurate determination of Du which
requires urine collection until drug excretion is complete.
3- Fluctuations in the rate of drug elimination and experimental errors
(such as incomplete bladder emptying) cause considerable departure
from linearity in the rate method.
4- The sigma-minus is less affected by fluctuations in the rate of drug
elimination.
5- The ku can be obtained from the rate method but not from the sigma-
minus method.
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 Problems in Obtaining Valid Urinary Excretion Data

1- A significant fraction of 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 the presence of metabolites.
3- Frequent sampling is necessary for a good curve description.
4- Urine samples should be collected until almost all drug is
excreted(approximately 8 t1/2).
5- Variation in urinary pH and volume cause significant variation in urinary
excretion rates.
6- Subjects should be instructed to the importance of complete bladder
emptying.

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Determination of total or renal clearance using AUC

 Total and renal clearance can be determined from the following equations
respectively

D ose
C lT = 
[ A U C ]0

Du
C lR = 
[ A U C ]0

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Fraction of drug excreted
The fraction of drug excreted unchanged in the
urine (fe) can be calculated as follows:


D ku
fe = u
=
Dose k

ku
ClR = ClT = f eClT
k
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 IV bolus administration
Monitoring drug in urine

If the administered drug is If the administered drug is

totally removed in urine in removed in urine in both
unmetabolized form unmetabolized form and
metabolized forms
1) Ku = K 1) Ku ≠ K
2) When t = ∞, e − k t = 0 2) (Du)∞ ≠ Do
therefore (Du)∞ = Do (Du)∞ = Ku. Do
K

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Determination of the non-renal rate constant (knr)

 knr = is the elimination rate constant for any route of

elimination other than renal excretion.
 k - ku = knr
 Since drug elimination occurs mainly through renal excretion
and metabolism,
 knr  km
 K (called elimination rate constant) = ke + km

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Sample problem 1
 Knowing that a drug is completely excreted in urine without
metabolism, its dose is 1000 mg and its elimination rate constant is 0.77
hr-1, calculate the total amount excreted in urine until 6 hours.

to K, therefore
k u: D
D u = 0
(1 − e − k t
)
k

0 . 7 7 x1 0 0 0
D u = (1 − e − 0.77 x 6
)
0.77

D u = 990 mg

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Sample problem 2
4000 mg of antibiotic with half life 0.9 hrs was administered IV to a
patient, and the total amount of drug excreted in urine 24 hours after
the injection was 2471 mg. The initial plasma concentration was 215
mg/L
Calculate:
a) Excretion rate constant
b) Renal clearance
c) Metabolic rate constant and metabolic clearance
d) Fraction of drug excreted unchanged in urine

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Thank You
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