A SEMINAR ONURINARY EXCRETION STUDIES By GANDHI SONAM MUKESHCHANDRA
Introduction: This method of assessing bioavailability is based on theprinciple that the urinary excretion of unchanged drug isdirectly proportional to the plasma concentration of drug. The study is particularly useful for drugs extensivelyexcreted unchanged in urine for ex; certain thiazide diureticsand sulfonamides and for drugs that have urine as the site ofaction, for Ex :urinary antiseptics such as nitrofurantoin andhexamine..
The method involve collection of urine at regular intervalsfor a time span equal to 7 biological half lives, analysis ofunchanged drug in the collected sample anddetermination of the amount of drug excreted in eachinterval and cumulative amount excreted. At each samplecollection, total emptying of bladder is necessary to avoiderrors resulting from addition of residual amount to thenext sample. Frequent sampling also essential in thebeginning in order to compute correctly the rate ofabsorption
The method has several advantages and disadvantages asbellow: 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.
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.
Disadvantages:One cannot however compute Vd and Clt from urine data alone.One must also remember that urinary excretion data is not an accurate substitutefor the plasma level data; the data can be employed as a rough estimate of thepharmacokinetic parameters.If the drug product provides a very slow drug release or if the drug has very longbiological half-life, the resulting low urinary drug concentration may be too dilute tobe assessed with accuracy.
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.
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.
excretion data obtained with a singledose 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.
The extant of bioavailability iscalculated 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
Acute phamacological response : When bioavailability measurement by pharmacokinetics is difficult,inaccurate or no reproducible, an acute pharmacologic effect such as change in ECGor 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 morevariable and accurate correlation between measured response and drug availablefrom the formulation is difficult
Therapeutic responce.: This method is based on observing the clinical responce to a drugformulation given to patients suffering from disease for which it is intended tobe used. A major drawback of this method is that quantitation of observedresponce is too improper to allow for reasonable assessment of relativebioavailability between two dosage forms of the same drug.
Determination of Ke from urinaryexcretion data The first-order elimination (and excretion) rateconstants can be computed from urine data by twomethods:1. Rate of excretion method2. Sigma-minus method.
1. Rate of excretion method:-The rate of urinary drug excretion dXu/dt is proportional to the amount of drug inthe body written as:Where, Ke = first-order urinary excretion rate constant The above equation states that a semilog plot of rate of excretion versus timeyields a straight line with slope –Ke/2.303.
2. Sigma-minus method:-A disadvanges of rate of excretion method in estimating Ke is that fluctuation in therate of drug elimination are observed to a high degree and in most instances, thedata are so scattered that an estimate is difficult. These problems can be minimizedby using the alternative approach called as sigma –minus method.Equation;Where, Xu= cumulative amount of drug excreted unchanged in urine at any time t.
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.