INTRODUCTION

Excretion is defined as the process where by drugs and their metabolites are irreversibly transferred from internal to external environment. The principle organs of excretion are kidneys called as RENAL EXCRETION. Other organs can also excrete such as lungs, liver, salivary glands and sweat glands called as NON-RENAL EXCRETION.

The principle organs of renal excretion are kidneys. Excretion of drug by kidneys is called as renal excretion.

The basic functional unit of kidney involved in excretrion is the Nephron. Each Nephron is made up of the glomerulus, proximal tubule, the loop of henle, the disital tubule and the collecting tubule.

The principle processes that determine the urinary excretion of a drug are 1.Glomerular filtration 2.Active tubular secretion 3.Active or passive tubular re absorption

Glomerular filtration and active tubular secretion tend to increase the concentration of drugs in lumen where as tubular reabsorption decrease it and prevents the movement of drug out of the body. Thus the rate of excretion can be given by equation : Rate of excretion =

Rate of Filtration + Rate of Secretion Rate of Reabsorption

Glomerular filtration is uni directional process where by most compounds ionized and or unionized are filtered except those that are bound to plasma proteins or blood cells behave as macro molecules.

The driving force for filtration through the glomerular is the hydrostatic pressure of blood flowing in the capillaries. Out of the 25% cardiac out put only 10% or 120 to 130 ml/min is filtered through the glomeruli.
This filtration rate is often measured by determining the renal clearance of inulin. Inulin is readily filtered in the glomerulus, and is not subject to tubular secretion or re-absorption. Thus inulin clearance is equal to the GFR.

Active tubular secretion : it is carrier mediated process which requires energy for transportation of compounds against concentration gradient. Two active tubular secretion mechanisms have been identified System for secretion of organic acids/anions: like penicillin's, salicylates, glucuronides, sulphates etc. and endogenous acids such uric acid. System for secretion of organic bases/cations: like morphine, hexamethonium and endogenous amines like catecholamine, choline, histamine etc. Not affected by pH.

TUBULAR REABSORPTION: tubular reabsorption occurs after glomerular filtration of drugs. It takes place along all renal tubule. Reabsorption of a drug is indicated when the excretion rate values are less than the GFR of 130 ml/min. Tubular reabsorption can either be an; 1. Active tubular reabsorption 2. Passive tubular reabsorption

Active re-absorption Seen with high threshold endogenous substances or nutrients that the body needs to conserve such as electrolytes, glucose, vitamins, amino acids etc. Uric acid is also actively re-absorbed. Very few drugs undergo reabsorption actively e.g. oxopurinol.

Passive reabsorption The membrane is readily permeable to lipids, so filtered lipid-soluble substances are extensively reabsorbed. At this site, the driving force for such a process is concentration gradient is established by the reabsorption of water. Thus, if a drug is non-ionized or in the unionized form it may be readily reabsorbed.

Diffusion of agents through the membrane depend upon the degree of ionization which in turn depends on the 1. pH of urine 2. pKa of the drug 3. Urine flow rate
Effect of Urine pH on tubular re-absorption: Many drugs are either weak bases or acids and therefore the pH of the filtrate can greatly influence the extent of tubular re-absorption for many drugs. When urine is acidic, weak acid drugs tend to be reabsorbed. Alternatively when urine is more alkaline, weak bases are more extensively reabsorbed These changes can be quite significant as urine pH can vary from 4.5 to 8.0 depending on the diet (e.g. meat can cause a more acidic urine) or food rich in carbohydrate pH or drugs (which can increase or decrease urine pH).

Alteration of Urine pH

Excretion of some drugs can be increased by suitable adjustment of urine pH e.g. pentobarbital (a weak acid) overdose may be treated by making the urine more alkaline with sodium bicarbonate injection. Effective if the drug is extensively excreted as the unchanged drug.
If the drug is extensively metabolized, then alteration of kidney excretion may not significantly alter the overall drug metabolism. The effect of pH change on tubular re-absorption can be predicted by consideration of drug pKa according to the Henderson-Hesselbalch equation.

For weak acids

pH = pKa + log (ionized drug) (un-ionized drug)

% drug ionized = 10(PH Pka) *100 1 + 10(PH Pka)

For weak bases pH = pKa + log (un- ionized drug) (ionized drug) % drug ionized = 10(PKa PH) *100 1 + 10(PKa Ph)

EFFECT OF DRUG Pka ON RENAL CLEARANCE:

The significance of pH dependent excretion for any particular compound is greatly dependent upon its pKa and lipid solubility. A characteristic of drugs, pKa values govern the degree of ionization at a particular pH. A polar and ionized drug will be poorly reabsorbed passively and excreted rapidly Reabsorption is also affected by the lipid solubility of drug; an ionized but lipophilic drug will be reabsorbed while an unionized but polar one will be excreted.

Very weakly acidic, nonpolar drugs (pKa>8.0) such as phenytoin or very weakly basic, nonpolar drugs (pKa< 6.0) such as propoxyphene are mostly unionized throughout the entire range of urine pH. The rate of excretion of such drugs is always low and insensitive to pH of urine.

A strongly acidic drug (pKa 2.0) such as cromoglycic acid or a strongly basic drug (pKa 12.0) such as guanethidine, is completely ionized at all values of urine pH and are , therefore, not reasorbed. Their rate of excretion is always high and insensitive to pH of urine.

Only for an acidic drug in the pKa range 3 8 eg NSAIDS and basics drug in pka range 6 12 eg morphine analogs and tricyclic antidepressants is the extent of re-absorption greatly dependent on urine pH.

URINE FLOW RATE:

In addition to urine pH and drug pKa, the rate of urine flow influence extent of re absorption. Polar drugs they are independent of pH are not reabsorbed, unaffected by urine flow rate. Only those drugs whose absorption is pH sensitive show dependence of urine flow rate. For such drugs reabsorption is irreversibly proportional to the urine flow rate.

CLEARANCE:
is defined as the hypothetical volume of body fluids containing drug from which the drug is removed or cleared completely from the body in a specified period of the time. It is expressed in ml/min, and is a constant for any given plasma drug concentration. Clearance relates plasma concentration to the rate of drug elimination.

Clearance (cl) =

elimination rate plasma drug concentration clearance is expressed as sum of the renal clearance and non-renal clearance.

RENAL CLEARANCE: The volume of plasma which is completely cleared of the unchanged drug by the kidney per unit time mathematically expressed as clR = Rate of urinary excretion plasma drug concentration

physiologically it is the ratio of sum of the rate of glomerular filtration and active secretion minus rate of reabsorption to plasma drug concentration C.

RC = rf+rs-rr/P
rf = rate of filtration rs = rate of secretion rr = rate of reabsorption

Renal clearance ml/min 0 (least value)

Mechanism of renal clearance

example

Drug filtered and glucose completely re absorbed Drug filtered and reabsorbed partially Lipophilic drugs

< 130

130

Drug is filtered only

Creatinine,inulin

>130

Drug filtered as well as Polar drugs secreted actively Clearance = renal plasma flow rate lodopyracet

650

 FACTORS AFFECTING RENAL EXCRETION

1.Plasma concentration of drug. 2.Distribution and Binding characteristic of drug. 3.Blood flow to the kidneys. 4.Biological factors. 5.Drug interactions. 6.Disease states.

PHYSICOCHEMICAL PROPERTIES OF DRUG : Like molecular size, pKa , lipid solubility Molecular size Drugs with Mol.wt <300 are excreted in kidney. Mol.wt 300 to 500 Dalton are excreted both through urine and bile.

BINDING CHARACTERISTICS OF THE DRUGS : Drugs that are bound to plasma proteins behave as macromolecules and cannot be filtered through glomerulus. Only unbound or free drug appear in glomerular filtrate. Protein bound drug has long half lives.

BIOLOGICAL FACTORS : Age, sex, species, strain difference etc alter the excretion of the drug. Sex Renal excretion is 10% lower in female than in males. Age The renal excretion in newborn is 30-40 % less in comparison to adults. Old age The GFR is reduced and tubular function is altered which results in slow excretion of drugs and prolonged half lives.

BLOOD FLOW TO THE KIDNEY :

Important in case of drug excreted by glomerular filteration and those are actively secreted only. Increase the perfusion enhance the elimination.

URINE FLOW RATE :

Polar drug are not affected by urine pH hence not get reabsorbed so unaffected by urine flow rate. Only those drugs whose reabsorption is pH

sensitive Ex. Weak acids and bases depend on urine flow rate. Urine flow
rate can be incresed by forced diuresis by large fluid intake or other diuretics.

DRUG INTERACTIONS :

Any drug interaction that result in alteration of binding characteristics, renal blood flow, active secretion, urine pH, and forced diuresis would alter renal clearance of drug.Alkalinization of urine with citrates and bicarbonates promote excretion of acidic drugs.

DISEASE STATE : RENAL DYSFUNCTION

Greatly cause the elimination of drugs those are primarily excreted by kidney. Some of the causes of renal failure are hypertention, Diabetes, hypovolemiya(low blood supply to kidney), heavy metals.
UREMIA Characterized by Impaired GF , accumulation of fluids & protein metabolites. Half life increased resulting in drug accumulation and increased toxicity.

Renal disease considerations If a drug is extensively excreted unchanged into urine, alteration of renal function will alter the drug elimination rate.

Creatinine clearance can be used as a measure of renal function.

For most drugs which are excreted extensively as unchanged drug, a good correlationhas been found between creatinine clearance and drug clearance or observed elimination rate (since Vd is usually unchanged).

DOSE ADJUSTMENT
Creatinine clearance

Creatinine is produced in the body by muscle metabolism from creatine phosphate.

Creatinine production is dependent on the age, weight, and sex of the patient. Elimination of creatinine is mainly by glomerular filtration with a small percentage by active secretion.

With the patient in stable condition the production is like a continuous infusion to steady state with the infusion rate controlled by muscle metabolism and the elimination controlled by renal function.

Thus as renal function is reduced, serum creatinine concentrations increases. Other compounds such as inulin are also used for GFR measurement. Involves collection of total urine and a plasma/serum determination at the mid-point time

ClR = Rate of creatitine excretion serum creatitine in mg% normal creatitine clearence value is 120 to 130 ml/min. avalue of 20 to 50 ml/min indicate moderate renal failure and below 10 ml/min denotes severe renal failure.

For males

for females

HAEMODIALYSIS
Haemodialysis or artificial kidney therapy is used in renal failure to remove toxic waste material normally removed by the kidneys, from the patients blood. Involves diversion of blood externally and allowed to flow across a semipermeable membrane bathed with an aqueous isotonic solution. Nitrogenous waste products and some drugs will diffuse from the blood, thus these compounds will be eliminated. Particularly important with drugs which: Have good water solubility; Are not tightly bound to plasma protein; Are smaller (less than 500) molecular weight; and Have a small apparent volume of distribution.

NON-RENAL ROUTE OF DRUG EXCRETION Various routes are ; Biliary Excretion Pulmonary Excretion Salivary Excretion Mammary Excretion Skin/dermal Excretion Gastrointestinal Excretion Genital Excretion

1 ) BILIARY EXCRETION : Bile juice is secreted by hepatic cells of the liver. Its important in the digestion and absorption of fats. 90% of bile acid is reabsorbed from intestine and transported back to the liver for resecretion. The metabolites are more excreted in bile than parent drugs due to increased polarity. Several factor influence secretion of drug in bile are; Molecular weight. Polarity. Nature of biotransformation. Other factor like sex, spices, disease state, drug interaction.

Nature of bio-transformation process:

Phase-II reactions mainly glucuronidation and conjugation with glutathione result in metabolites with increased polarity and molecular weight for biliary excretion. Ex. of drugs excreted in the bile are chloromphenicol, morphine and indomethacin. For a drug to be excreted in bile must have polar groups like COOH, -SO3H. Conjugation with amino acids ,acetylation ,methylation do not result in metabolites with high molecular weight and polarity hence little influence on biliary excretion.

Efficacy of drug excretion by biliary system can be tested by an agent that is completely eliminated in bile, Ex. sulfobromophthalein. This marker is excreted in half an hour in intestine when hepatic function is normal. Delay in its excretion indicates hepatic and biliary malfunction. Some drugs which are excreted as glucuronides or as glutathione conjugates are hydrolyzed by intestinal or bacterial enzymes to the parent drugs which are reabsorbed. The reabsorbed drugs are again carried to the liver for resecretion via bile into the intestine.

This phenomenon of drug cycling between the intestine & the liver is called Enterohepatic circulation Enterohepatic Circulation is important in conservation of vitamins, folic acid and hormones. This process results in prolongation of half lives of drugs like DDT, oral contraceptives.

2 ) PULMONARY EXCRETION :
Gaseous and volatile substances such as general anesthetics (Halothane) are absorbed through lungs by simple diffusion. Pulmonary blood flow, rate of respiration and solubility of substance effect pulmonary excretion. Intact gaseous drugs are excreted but not metabolites. Alcohol which has high solubility in blood and tissues are excreted slowly by lungs.

3 ) SALIVARY EXCRETION :
The pH of saliva varies from 5.8 to 8.4. Unionized lipid soluble drugs are excreted passively. The bitter taste in the mouth of a patient is indication of drug excreted. Some basic drugs inhibit saliva secretion and are responsible for mouth dryness. Compounds excreted in saliva are Caffeine, Phenytoin, Theophylline.

4 ) MAMMARY EXCRETION :
Milk consists of lactic secretions which is rich in fats and proteins. 0.5 to one litre of milk is secreted per day in lactating mothers. Excretion of drug in milk is important as it gains entry in breast feeding infants.

5 ) SKIN EXCRETION : Drugs excreted through skin via sweat follows pH partition hypothesis. Excretion of drugs through skin may lead to urticaria and dermatitis. Compounds like benzoic acid, salicylic acid, alcohol and heavy metals are excreted in sweat. 6 ) GASTROINTESTINAL EXCRETION : Excretion of drugs through GIT usually occurs after parenteral administration. Water soluble and ionized form of weakly acidic and basic drugs are excreted in GIT. Example are nicotine and quinine are excreted in stomach. Drugs excreted in GIT are reabsorbed into systemic circulation & undergo recycling.

EXCRETION PATHWAYS, TRANSPORT MECHANISMS & DRUG EXCRETED.

REFERENCES: Brahmankar M D., Jaiswal S B., Biopharmaceutics and Pharmacokinetics A Treatise vallabh prakasan I edition 2002, p.no;178192. Shrgel L., Wu-Pong S., Yu A B C., Applied Biopharmaceutics & Pharmacokinetics V edition 2005.

Venkateswarlu V., Biopharmaceutics and Pharmacokinetics II edition 2008, PharmaMed Press.

Gibaldi M., Biopharmaceutics and Clinical Pharmacokinetics IV edition 2006.