Factors Affecting Renal Excretion or Renal Clearance

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Chapter: Biopharmaceutics and Pharmacokinetics : Excretion of Drugs

Apart from the three physiologic processes that govern the urinary excretion, other factors influencing renal clearance of drugs and metabolites are:


Apart from the three physiologic processes that govern the urinary excretion, other factors influencing renal clearance of drugs and metabolites are:

1. Physicochemical properties of the drug

2. Plasma concentration of the drug

3. Distribution and binding characteristics of the drug

4. Urine pH

5. Blood flow to the kidneys

6. Biological factors

7. Drug interactions

8. Disease states


1. Physicochemical Properties of the Drug

Important physicochemical factors affecting renal excretion of a drug are - molecular size, pKa and lipid solubility. The molecular weight of a drug is very critical in its urinary elimination. An agent of small molecular size can be easily filtered through the glomerulus. Compounds of weights below 300 Daltons, if water-soluble, are readily excreted by the kidneys. Drugs in the molecular weight range 300 to 500 Daltons can be excreted both in urine and bile. Molecules of size greater than 500 Daltons are excreted in urine to a lesser extent (see table 6.3).

The influence of drug pKa on excretion has already been discussed. Urinary excretion of an unchanged drug is inversely related to its lipophilicity. This is because, a lipophilic drug is passively reabsorbed to a large extent.

Stereochemical nature of the drug may also influence renal clearance. If a drug exhibits stereoselective protein binding then the drug enantiomers would exhibit differential filtration rates. Active tubular secretion being an active process may also demonstrate stereoselectivity for some drugs. Indeed, numerous drugs such as chloroquine, disopyramide and terbutaline have been found to be stereoselectively secreted by the kidneys. Active tubular reabsorption also demonstrates these effects as in the case of certain endogenous substances such as glucose and amino acids. Passive reabsorption is unaffected.

2. Plasma Concentration of the Drug

Glomerular filtration and reabsorption are directly affected by plasma drug concentration since both are passive processes. A drug that is not bound to plasma proteins and excreted by filtration only, shows a linear relationship between rate of excretion and plasma drug concentration. In case of drugs which are secreted or reabsorbed actively, the rate process increases with an increase in plasma concentration to a point when saturation of carrier occurs. In case of actively reabsorbed drugs, excretion is negligible at low plasma concentrations. Such agents are excreted in urine only when their concentration in the glomerular filtrate exceeds the active reabsorption capacity, e.g. glucose. With drugs that are actively secreted, the rate of excretion increases with increase in plasma concentration up to a saturation level. These situations are depicted in Fig. 6.3.

3. Distribution and Binding Characteristics of the Drug

Clearance is inversely related to apparent volume of distribution of drugs. A drug with large Vd is poorly excreted in urine. Drugs restricted to blood compartment have higher excretion rates.

Drugs that are bound to plasma proteins behave as macromolecules and thus cannot be filtered through the glomerulus. Only unbound or free drug appear in the glomerular filtrate. An earlier equation given for renal clearance is:

ClR = ( Urine drug concentration / concentrat drug Plasma ion ) / rate flow Urine      (6.8)

Since only free drug can be excreted in the urine, the fraction of drug bound to plasma proteins is important and can be computed from equation:

fu = Cu/C     (6.13)

where, fu = fraction of unbound drug in plasma,

Cu = concentration of unbound drug in plasma, and

C = total plasma concentration of drug.

Thus, equation 6.8 can be written as:

ClR fu . Urine flow rate (6.14)

Drugs extensively bound to proteins have long half-lives because the renal clearance is small and urine flow rate is just 1 to 2 ml/min. The renal clearance of oxytetracycline which is 66% unbound is 99 ml/min while that of doxycycline (7% unbound) is just 16 ml/min.

Actively secreted drugs are much less affected by protein binding, e.g. penicillins. The free fraction of such drugs are filtered as well as secreted actively and dissociation of drug-protein complex occurs rapidly.

The influence of urine pH on renal clearance has already been discussed.

5. Blood Flow to the Kidneys

The renal blood flow is important in case of drugs excreted by glomerular filtration only and those that are actively secreted. In the latter case, increased perfusion increases the contact of drug with the secretory sites and enhances their elimination. Renal clearance in such instances is said to be perfusion rate-limited.

6. Biological Factors

Age, sex, species and strain differences, differences in the genetic make-up, circadian rhythm, etc. alter drug excretion. Renal excretion is approximately 10% lower in females than in males. The renal function of newborns is 30 to 40% less in comparison to adults and attains maturity between 2.5 to 5 months of age. In old age, the GFR is reduced and tubular function is altered, the excretion of drugs is thus slowed down and half-life is prolonged.

7. Drug Interactions

Any drug interaction that results in alteration of protein-drug binding characteristics, renal flood flow, active secretion, urine pH and intrinsic clearance and forced diuresis would alter renal clearance of a drug.

Alteration in P-D binding: The renal clearance of a drug extensively bound to plasma proteins is increased after displacement with another drug. An interesting example of this is gentamicin induced nephrotoxicity by furosemide. Furosemide does not precipitate this effect by its diuretic effect but by displacing gentamicin from binding sites. The increased free antibiotic concentration accelerates its renal clearance.

Alteration of Urine pH: Acidification of urine with ammonium chloride, methionine or ascorbic acid enhances excretion of basic drugs. Alkalinisation of urine with citrates, tartarates, bicarbonates and carbonic anhydrase inhibitors promote excretion of acidic drugs.

Competition for Active Secretion: Phenylbutazone competes with hydroxyhexamide, the active metabolite of antidiabetic agent acetohexamide, for active secretion and thus prolongs its action.

Probenicid is a competitive inhibitor of organic anion transport system.

Cimetidine is competitive inhibitor of organic cation transport system.

Forced Diuresis: All diuretics increase elimination of drugs whose renal clearance gets affected by urine flow rate.

8. Disease States—Renal Impairment

Renal dysfunction greatly impairs the elimination of drugs especially those that are primarily excreted by the kidneys. Some of the causes of renal failure are hypertension, diabetes mellitus, hypovolemia (decreased blood supply to the kidneys), pyelonephritis (inflammation of kidney due to infections, etc.), nephroallergens (e.g. nephrotoxic serum) and nephrotoxic agents such as aminoglycosides, phenacetin and heavy metals such as lead and mercury.

Uraemia, characterized by impaired glomerular filtration and accumulation of fluids and protein metabolites, also impairs renal clearance of drugs. In both these conditions, the half-lives of drugs are increased. As a consequence, drug accumulation and toxicity may result. Determination of renal function is therefore important in such conditions in order to monitor the dosage regimen.

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