Renal Excretion

RENAL EXCRETION

The kidney is responsible for excreting all water soluble substances. The amount of drug or its metabolites ultimately present in urine is the sum total of glomerular filtration, tubular reabsorption and tubular secretion (Fig. 3.2).

Net renal ₌ (Glomerular filtration + tubular excretion)

Glomerular Filtration

Glomerular capillaries have pores larger than usual; all nonprotein bound drug (whether lipidsoluble or insoluble) presented to the glomerulus is filtered. Thus, glomerular filtration of a drug depends on its plasma protein binding and renal blood flow. Glomerular filtration rate (g.f.r.), normally ~ 120 ml/min, declines progressively after the age of 50, and is low in renal failure.

Tubular Reabsorption

This occurs by passive diffusion and depends on lipid solubility and ionization of the drug at the existing urinary pH. Lipidsoluble drugs filtered at the glomerulus back diffuse in the tubules because 99% of glomerular filtrate is reabsorbed, but nonlipidsoluble and highly ionized drugs are unable to do so. Thus, rate of excretion of such drugs, e.g. aminoglycoside antibiotics, quaternary ammonium compounds parallels g.f.r. (or creatinine clearance). Changes in urinary pH affect tubular reabsorption of drugs that are partially ionized

          Weak bases ionize more and are less reabsorbed in acidic urine.

          Weak acids ionize more and are less reabsorbed in alkaline urine.

This principle is utilized for facilitating elimination of the drug in poisoning, i.e. urine is alkalinized in barbiturate and salicylate poisoning. Though elimination of weak bases (morphine, amphetamine) can be enhanced by acidifying urine, this is not practiced clinically, because acidosis can induce rhabdomyolysis, cardiotoxicity and actually worsen outcome. The effect of changes in urinary pH on drug excretion is greatest for those having pKa values between 5 to 8, because only in their case pH dependent passive reabsorption is significant.

Tubular Secretion

This is the active transfer of organic acids and bases by two separate classes of relatively nonspecific transporters (OAT and OCT) which operate in the proximal tubules. In addition, efflux transporters Pgp and MRP2 are located in the luminal membrane of proximal tubular cells. If renal clearance of a drug is greater than 120 mL/min (g.f.r.), additional tubular secretion can be assumed to be occurring.

Active transport of the drug across tubules reduces concentration of its free form in the tubular vessels and promotes dissociation of protein bound drug, which again is secreted (Fig. 3.2). Thus, protein binding, which is a hinderance for glomerular filtration of the drug, is not so (may even be facilitatory) to excretion by tubular secretion.

 (a) Organic acid transport (through OATP ) for penicillin, probenecid, uric acid, salicylates, indomethacin, sulfinpyrazone, nitrofurantoin, methotrexate, drug glucuronides and sulfates, etc.

 (b) Organic base transport (through OCT) for thiazides, amiloride, triamterene, furosemide, quinine, procainamide, choline, cimetidine, etc.

Inherently both transport processes are bidirectional, i.e. they can transport their substrates from blood to tubular fluid and vice versa. However, for drugs and their metabolites (exogenous substances) secretion into the tubular lumen predominates, whereas an endogenous substrate like uric acid is predominantly reabsorbed.

Drugs utilizing the same active transport compete with each other. Probenecid is an organic acid which has high affinity for the tubular OATP. It blocks the active transport of both penicillin and uric acid, but whereas the net excretion of the former is decreased, that of the latter is increased.

This is because penicillin is primarily secreted while uric acid is primarily reabsorbed. Many drug interactions occur due to competition for tubular secretion, e.g.

Salicylates block uricosuric action of probenecid and sulfinpyrazone and decrease tubular secretion of methotrexate.

Probenecid decreases the concentration of nitrofurantoin in urine, increases the duration of action of penicillin/ampicillin and impairs secretion of methotrexate.

Sulfinpyrazone inhibits excretion of tolbutamide.

Quinidine decreases renal and biliary clearance of digoxin by inhibiting efflux carrier Pgp.

Tubular transport mechanisms are not well developed at birth. As a result, duration of action of many drugs, e.g. penicillin, cephalosporins, aspirin is longer in neonates. These systems mature during infancy. Renal function again progressively declines after the age of 50 years; renal clearance of most drugs is substantially lower in the elderly (>75 yr).