Flows through the vessels surrounding the tubule because there will be a concentration gradient in the direction tubuleblood Water soluble molecules

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which are ionized at the pH of the tubular fluid will not be reabsorbed by passive diffusion and will pass out into the urine.

Certain molecules, such as ^-aminohippuric acid (figure 3.18), a metabolite of /-aminobenzoic acid are actively transported from the bloodstream into the tubules by a specific anion transport system. Organic anions and cations appear to be transported by separate transport systems located on the proximal convoluted tubule. Active transport is an energy requiring process and therefore may be inhibited by metabolic inhibitors, and there may be competitive inhibition between endogenous and foreign compounds. For example, the competitive inhibition of the active excretion of uric acid by compounds such as probenecid may precipitate gout.

Passive diffusion of compounds into the tubules is proportional to the concentration in the bloodstream, so the greater the amount in the blood, the greater will be the rate of elimination. However, when excretion is mediated via active transport or facilitated diffusion, which involves the use of specific carriers, the rate of elimination is constant and the carrier molecules may become saturated by large amounts of compound. This may have important toxicological consequences. As the dose of a compound is increased the plasma level will increase. If excretion is via passive diffusion the rate of excretion will increase as this is proportional to the plasma concentration. If excretion is via active transport, however, increasing the dose may lead to saturation of renal elimination and a toxic level of compound in the plasma and tissues may be reached.

Another factor which may affect excretion is binding to plasma proteins. This may reduce excretion via passive diffusion, especially if binding is tight and extensive, as only the free portion will be filtered or will passively diffuse into the tubule. Protein binding does not affect active transport however and a compound such as /-aminohippuric acid (figure 3.18), which is 90% bound to plasma proteins, is cleared in the first pass of blood through the kidney.

One of the factors which affects excretion is the urinary pH. If the compound which is filtered or diffuses into the tubular fluid is ionized at the pH of that fluid, it will not be reabsorbed into the bloodstream by passive diffusion. For example, an acidic drug such as phenobarbital is ionized at alkaline urinary pH and a basic drug such as amphetamine is ionized at an acidic urinary pH. This factor is utilized in the treatment of poisoning with barbiturates and salicylic acid for example (see Chapter 7). Thus by giving sodium bicarbonate to the patient, the urine becomes more alkaline and excretion of acidic metabolites is increased. The pH of urine may be affected by diet; high protein diet for instance causes urine to become more acid. The rate of urine flow from the kidney into the bladder is also a factor in the excretion of foreign compounds; high fluid intake, and therefore production of copious urine, will tend to facilitate excretion. Factors which affect kidney function such as age and disease will influence urinary excretion and may therefore increase toxicity by reducing elimination from the body. For example, sale of the antiarthritic drug benoxaprofen was stopped as it caused liver damage and other adverse effects. This was probably a result of accumulation following repeated and inappropriate doses of the drug given to elderly patients whose kidney function was reduced.

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