This document provides information on urinary excretion studies, a method used to assess bioavailability of drugs that are excreted unchanged in urine. It discusses how the method involves collecting urine samples at regular intervals over multiple biological half-lives and analyzing drug levels. It notes advantages like being noninvasive and allowing calculation of pharmacokinetic parameters. The document outlines criteria for valid studies and methods to determine elimination rate constants and bioavailability from urinary excretion data.
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies.
The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are
Model approach, and
Model-independent approach (also called as non-compartmental analysis).
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies.
The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are
Model approach, and
Model-independent approach (also called as non-compartmental analysis).
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Methods for Measurement of bioavailability pharmacampus
Which are the Methods for Measurement of bioavailability?- Pharmacokinetic method- Plasma level time studies, Urinary excretion studies.
Pharmacodynamic method: Acute pharmacologic response, Therapeutic response.
CONCEPT OF LOADING AND MAINTAINANCE DOSE.pptxNamrataSawant19
Most drugs for chronic condition are prescribed in a dosage regimen is based on the administration of a fixed constant dose(D) at fixed regular dosing intervals(T) for long period of time.
The D & T recommended by the manufacturer is based on the effective therapeutic concentration of drug in the plasma needed to treat the chronic condition.
Primary purpose of using loading dose in therapeutic treatment is to attain steady-state concentration of the drug as quickly as possible, usually right from the start of the dosage regimen for the treatment.
Methods For Assesment Of Bioavailability Anindya Jana
Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Methods for Measurement of bioavailability pharmacampus
Which are the Methods for Measurement of bioavailability?- Pharmacokinetic method- Plasma level time studies, Urinary excretion studies.
Pharmacodynamic method: Acute pharmacologic response, Therapeutic response.
CONCEPT OF LOADING AND MAINTAINANCE DOSE.pptxNamrataSawant19
Most drugs for chronic condition are prescribed in a dosage regimen is based on the administration of a fixed constant dose(D) at fixed regular dosing intervals(T) for long period of time.
The D & T recommended by the manufacturer is based on the effective therapeutic concentration of drug in the plasma needed to treat the chronic condition.
Primary purpose of using loading dose in therapeutic treatment is to attain steady-state concentration of the drug as quickly as possible, usually right from the start of the dosage regimen for the treatment.
Methods For Assesment Of Bioavailability Anindya Jana
Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
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Urinaryexcreation studies
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.