Tubular secretion drug transport

The co-administration of drugs which inhibit the transporters involved in renal tubular secretion can reduce the urinaty excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, probenecid increases the plasma concentration and the duration of effect of penicillin by inhibiting its renal tubular secretion. It also elevates the plasma concentration of methotrexate by the same mechanism, provoking its toxic effects. 

Tubular secretion is the transfer of substances from the peritubular capillaries into the renal tubule for excretion in urine. This process is particularly important for the regulation of potassium and hydrogen ions in the body it is also responsible for removal of many organic compounds from the body. These may include metabolic wastes as well as foreign compounds, including drugs such as penicillin. Most substances are secreted by secondary active transport. 

It is important to appreciate that these tubular transport mechanisms are not as well developed in the neonate as in the adult. In addition, their functional capacity may be diminished in the elderly. Thus, compounds normally eliminated by tubular secretion will be excreted more slowly in the very young and in the older adult. This age dependence of the rate of renal drug secretion may have important therapeutic implications and must be considered by the physician who prescribes drugs for these age groups. 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

The uricosuric drugs (or urate diuretics) are anions that are somewhat similar to urate in structure therefore, they can compete with uric acid for transport sites. Small doses of uricosuric agents will actually decrease the total excretion of urate by inhibiting its tubular secretion. The quantitative importance of the secretory... 

Tubular secretion The active secretory systems can rapidly remove the protein-bound drugs from the blood and transport them into tubular fluid as the drugs that are bound to proteins are not readily available for excretion by filtration. The drugs known to be secreted by organic anion secretory system (i.e. strong acids) are salicylates, chlorothiazide, probenecid, penicillin etc. and cation (i.e. bases) includes catecholamines, choline, histamine, hexamethonium, morphine etc. 

Proximal tubular secretion is an energy-dependent active-transport mechanism. Specific high-affinity proteins in the proximal tubule transport drugs into the tubule for elimination via the urine. These proteins can also remove acidic and basic drugs from plasma protein-binding sites and transport them into the tubule. Since it is carrier-mediated, this mechanism is a saturable system. Therefore, other drugs may also compete for transport where similar carriers are employed. 

Drug metabolism, renal tubular secretion, and biliary secretion are usually mediated by metabolizing enzymes or transporter proteins. These protein systems usually possess good substrate selectivity with finite capacities, which are described by the Michaelis-Menten equation,... 

Urakami Y, Okuda M, Masuda S, et al. Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Exp Ther 1998 287 800-805. 

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. 

For example, coadministration of the drug probenecid reduces the tubular secretion of penicillin G because both are organic acids that are transported by a common carrier. The oral administration of probenecid in conjunction with penicillin G results in higher and more prolonged concentrations of the antibiotic in plasma than with penicillin alone. The elevation in plasma penicillin level can be at least twofold and sometimes much greater. The ability to reduce the dose of the antibiotic required is particularly important in the treatment of resistant infections. 

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