1. A
SEMINAR
ON
URINARY EXCRETION STUDIES
By
GANDHI SONAM MUKESHCHANDRA
2. Introduction:
This method of assessing bioavailability is based on the
principle that the urinary excretion of unchanged drug is
directly proportional to the plasma concentration of drug.
The study is particularly useful for drugs extensively
excreted unchanged in urine for ex; certain thiazide diuretics
and sulfonamides and for drugs that have urine as the site of
action, for Ex :urinary antiseptics such as nitrofurantoin and
hexamine..
3. The method involve collection of urine at regular intervals
for a time span equal to 7 biological half lives, analysis of
unchanged drug in the collected sample and
determination of the amount of drug excreted in each
interval and cumulative amount excreted. At each sample
collection, total emptying of bladder is necessary to avoid
errors resulting from addition of residual amount to the
next sample. Frequent sampling also essential in the
beginning in order to compute correctly the rate of
absorption
4. The method has several advantages and disadvantages as
bellow:
Advantages:
The method is useful when there is lake of sufficiently sensitive analytical
techniques to measure concentration of drugs in plasma with accuracy.
The method is noninvasive and therefore better subject compliance is assured.
Convenience of collecting urine samples in comparison to drawing of blood
periodically.
Often, a less sensitive analytical method is required for determining urine drug
concentration as compared to plasma concentration; if the urine drug
concentration are low, assaying of larger sample volumes is relatively easy.
5. First-order elimination, excretion and absorption rate constants and fraction
excreted unchanged can be computed from such data; first order metabolism or
external excretion rate constant can also be calculated subsequently from the
difference (kE –ke) =km.
Direct measurement of bioavailability, both absolute and relative, is possible
without the necessary of fitting the data to a mathematical modal.
When coupled with plasma level-time data, it can also be used to estimate renal
clearance of unchanged drug according to following equation:
If Vd is know, total systemic clearance and nonrenal clearance can also be calculated.
6. Disadvantages:
One cannot however compute Vd and Clt from urine data alone.
One must also remember that urinary excretion data is not an accurate substitute
for the plasma level data; the data can be employed as a rough estimate of the
pharmacokinetic parameters.
If the drug product provides a very slow drug release or if the drug has very long
biological half-life, the resulting low urinary drug concentration may be too dilute to
be assessed with accuracy.
7. Criteria for obtaining valid urinary excretion data:
A significant amount of drug must be excreted unchanged in the urine (at least
10%).
The analytical method must be specific for the unchanged drug ; metabolites
should not interfere.
Water-loading should be done by taking 400 ml of water after fasting overnight,
to promote diuresis and enable collection of sufficient urine samples.
Before administration of drug, the bladder must be emptied completely after 1
hour from water-loading and the urine sample taken as blank; the drug should
then be administration with 200 ml of water and should be followed by 200 ml
given at hourly intervals for the next 4 hours.
Volunteers must be instructed to completely empty their bladder while
collecting urine samples.
8. Frequent sampling should be done in order in order to obtain a good curve.
During sampling, the exact time and volume of urine excreted should be
noted.
An individual collection period should not exceed one biological half-life of
the drug and ideally should be considerably less.
Urine samples must be collected for at least 7 biological half-lives in order to
ensure collection of more than 99% of excreted drug.
Changes in urine pH and urine volume may alter the urinary excretion rate.
9. excretion data obtained with a single
dose study are;
1.(dXu/dt)max: The maximum urinary excretion rate, it is obtained from the peak of
plot between rate of excretion versus mid point time of urine collection period. It is
analoguous to the Cmax derived from plasma level studies since the rate of apparance
of drug in urine is proportional to its concentration in systemic circulation. its value
increases as the rate of extent of absorption increases.(as shown in bellow fig.)
2.(tu)max : The time for maximum excertion rate ,it is analogous to the t max of plasma
level data.Its value decreases as the absoption rate increases.
3.Xu : The cumulative amount of drug excreted in the urine, it is related to the AUC of
plasma level data and increases as the extent of absorption increases.
10.
11.
12. The extant of bioavailability is
calculated from equation given below:
Absolute bioavailability:
F = [ Xu]∞ oral x [Dose] iv
[Xu ]∞ i.v x [Dose] oral
Relative bioavailability:
Fr = [ Xu]∞ test x [Dose] std
[Xu]∞ std x [Dose] test
With multiple dose study to steady state, the eq for computing
bioavailability is:
Fr = [ Xu,ss]∞ test x [Dose] std
[Xu,ss]∞ std x [Dose] test
13. Acute phamacological response :
When bioavailability measurement by pharmacokinetics is difficult,
inaccurate or no reproducible, an acute pharmacologic effect such as change in ECG
or EEG reading, pupil diameter, etc is related to the time course of a given drug.
Bioavailability can then be determined by construction of pharmacologic effect –
time curve as well as dose – response graphs.
A disadvantages of this method is that the pharmacologic response tends to be more
variable and accurate correlation between measured response and drug available
from the formulation is difficult
14. Therapeutic responce.:
This method is based on observing the clinical responce to a drug
formulation given to patients suffering from disease for which it is intended to
be used. A major drawback of this method is that quantitation of observed
responce is too improper to allow for reasonable assessment of relative
bioavailability between two dosage forms of the same drug.
15. Determination of Ke from urinary
excretion data
The first-order elimination (and excretion) rate
constants can be computed from urine data by two
methods:
1. Rate of excretion method
2. Sigma-minus method.
16. 1. Rate of excretion method:-
The rate of urinary drug excretion dXu/dt is proportional to the amount of drug in
the body written as:
Where,
Ke = first-order urinary excretion rate constant
The above equation states that a semilog plot of rate of excretion versus time
yields a straight line with slope –Ke/2.303.
17. 2. Sigma-minus method:-
A disadvanges of rate of excretion method in estimating Ke is that fluctuation in the
rate of drug elimination are observed to a high degree and in most instances, the
data are so scattered that an estimate is difficult. These problems can be minimized
by using the alternative approach called as sigma –minus method.
Equation;
Where,
Xu= cumulative amount of drug excreted unchanged in urine at any time t.
18. References:
Textbook of Biopharmaceutics & Pharmacokinetics by Dr.Shobha Rani R.
Fundamentals of Biopharmaceutics & Pharmacokinetics by V.Venkateswarlu.
Biopharmaceutics & Pharmacokinetics. A Treatise by D.M.Brahmankar &Sunil
B.Jaiswal.
