DRUG KINETICS-PART-13-RENAL CLEARANCE

RENAL CLEARANCE

Renal clearance is one of the major routes of excretion for hydrophilic polar drugs which means all water soluble substances are excreted through kidneys.

Kidneys are excreting the drug by glomerular filtration and active tubular secretion.

Glomerular filtration is a passive filter process in which smaller molecules are filtered through the fine meshwork in the glomerulus of the nephron.

Albumin like plasma proteins are large molecules and cannot pass through the glomerular mesh work and hence drugs bound up with this proteins escapes from filtration.

Endogenous renal excretory substances such as creatinine and insulin are not actively secreted or reabsorbed but filtered through glomerulus.Hence they are used as a marker to measure the glomerular filter rate (GFR)

Tubular Reabsorption is a passive process in which the Fick's Law Of Diffusion is applicable.

The Fick's Law states that a solute from the region of higher concentration moves to the region of lower concentration across a concentration gradient with an assumption that all the regions are in a steady state level.

1.Fat soluble substances are reabsorbed from the interstitial cells of the lumen of the nephron back to the blood stream.

2.For weak electrolytes urine pH affects the ratio of non ionized and ionized drug.If the drug is primarily non ionized lipophilic form then it is reabsorbed by the lumen of the nephron back to the blood.On contrary if the drug is primarily in a polar,ionized hydrophilic form then it is excreted through the urine.

In more acidic urine excretion of weak acids are retarded.If the urine pH is increased by alkalinization of the urine for example by the administration of sodium bicarbonate,weak acids like salicylic acids are excreted more easily.

Administration of diuretics induce diuresis which causes increased urine flow and decrease in the time for reabsorption and the result is more drugs are excreted.

Active Tubular Secretion (ATS) which involves carrier mediated active transport system that require energy.

Two types of ATS systems are available in the kidneys.One for weak acids and another for weak bases.

The ATS systems are competition based.For example probenecid a weak acid competes for the same system with penicillin which is some what stronger yet another weak acid and thereby decreasing the excretion of penicillin.

The renal clearance of drugs that are actively secreted such as p-aminohippurate (PAH) is used to measure Effective Renal Blood Flow(ERBF)

Renal Clearance is defined as the volume of the drug present in the plasma that is removed by the kidney per unit time.The units are available as ml/min or L/hr.

Renal clearance (ClR) can be calculated as follows,

     ClR  =Rate of drug excretion/Cp =(dDU/dt)/Cp

Where Cp plasma concentration,DU is the drug in the urine,and dDU/dt is the rate of drug excretion.

The renal clearance can also be expressed by another equation as follows,

              ClR  =keVD  where ke is the first order renal excretion rate constant and VD is volume of the drug distributed.

                ClR = DU power infinity/AUC

                   where DU to the power infinity or steady state is the total amount of unchanged parent compound excreted in the urine and AUC is the Area Under Curve.

Renal Clearance can also be measured with the mechanism of getting clearance ratio which relates drug clearance to insulin (GFR) as follows:-

1.If the clearance ratio is < 1 the mechanism for drug clearance may result from filtration and reabsorption.

2.If the ratio = 1 the mechanism is by filtration only

3.If the ratio is > 1 the mechanism may be by filtration and active tubular secretion.