Glomerular filtration drug transport

Apart from glomerular filtration (B), drugs present in blood may pass into urine by active secretion. Certain cations and anions are secreted by the epithelium of the proximal tubules into the tubular fluid via special, energyconsuming transport systems. These transport systems have a limited capacity. When several substrates are present simultaneously, competition for the carrier may occur (see p. 268). 

Metabolites of the cholinesterase inhibitors and in some instances significant amounts of the parent compound are eliminated in the urine. Renal excretion is very important in the clearance of agents such as neostigmine, pyridostigmine, and edrophonium. This is demonstrated by a twofold to threefold increase in elimination half-lives for these drugs in anephric patients. Renal elimination is largely the result of glomerular filtration but probably also involves, at least in the case of quaternary amines, secretion via the renal cationic transport system. 

Renal handling of uric acid. Uric acid may be actively reabsorbed from the ultrafiltrate following its glomerular filtration or it may be secreted from the blood across the basolateral membrane into the proximal tubular cell. Both passive and active transport mechanisms are involved in the handling of urate. Uricosuric drugs at appropriate doses interfere with these processes. 

When probenecid (ColBENEMID) is given in sufficient amounts, it will block the active reabsorption of uric acid in the proximal tubules following its glomerular filtration, thereby increasing the amount of urate eliminated. In contrast, low dosages of probenecid appear to compete preferentially with plasma uric acid for the proximal tubule anionic transport system and thereby block its access to this active secretory system. The uricosuric action of probenecid, however, is accounted for by the drug s ability to inhibit the active reabsorption of filtered urate. 

Age In newborn infants, the glomerular filtration rate and tubular transport is immature, which takes 5 to 7 months to mature. Also, the hepatic drug metabolism capacity is also inadequate (that is why chloramphenicol can produce grey baby syndrome ), and due to the higher permeability of blood brain barrier, certain drugs attain high concentration in the CNS. 

Because carrier systems are involved, the secretory process has a limited carrying capacity and can be saturated. Therefore, in distinction from glomerular filtration, tubular secretion is dependent upon the plasma concentration of the drug. Like all active transport processes, secretion of a drug into the tubular fluid can be competitively inhibited by other drugs that are transported by the same carrier. 

Pharmacokinetics Unlike most of the alkylating agents, cyclophosphamide and ifosfamide are preferentially administered by the oral route. Minimal amounts of the parent drug are excreted into the feces (after biliary transport), or into the urine by glomerular filtration. 

Each day the body produces 1801 of glomerular filtrate which is modified in its passage down the renal tubules to appear as 1.51 of urine. Thus a 1% reduction in reabsorption of tubular fluid will more than double urine output. Clearly, drugs that act on the tubule have considerable scope to alter body fluid and electrolyte balance. Most clinically useful diuretics are organic anions, which are transported directly from the blood into tubular fluid. The following brief account of tubular function with particular reference to sodium transport will help to explain where and how diuretic drugs act it should be read with reference to Figure 26.1. 

The kidneys receive a large blood flow (approximately a quarter of the total cardiac output of 5 litres per minute) and from this volume of blood approximately 170 litres of filtrate are produced every day Clearly, the body would quickly become dehydrated if this volume of fluid were lost to the sewage system, so most of it is reabsorbed from the kidney tubule and returned to the bloodstream. Small molecules that are dissolved in the glomerular filtrate are also reabsorbed back into the bloodstream, either by passive diffusion (which obeys Fick s law) or by the utilisation of energy in an active transport process similar to the mechanisms for gut absorption discussed previously. It should be realised that reabsorption from the glomerular filtrate and return to the bloodstream are involved in the duration of action of many drugs, and a drug molecule may be filtered and reabsorbed many times before it is finally excreted from the body. 

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