Tubular secretion drug excretion

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. 

The renal excretion of drugs depends on glomerular filtration, tubular secretion, and tubular absorption. A twofold increase in glomerular filtration occurs in the first 14 days of life [36], The glomerular filtration rate continues to increase rapidly in the neonatal period and reaches a rate of about 86 mL/min per 1.73 m2 by 3 months of age. Children 3-13 years of age have an average clearance of 134 mL/min per 1.73 m2 [37]. Tubular secretion approaches adult values between 2 and 6 months [11], There is more variability observed in maturation of tubular reabsorption capacity. This is likely linked to fluctuations in urinary pH in the neonatal period [38],... 

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. 

The absorption and excretion of carbenicillin in man has been reported [396]. The antibiotic is not absorbed intact from the gut intramuscular injection (which is painful) often provides adequate serum levels (approximately 20 Mg/ntl) but infections with Pseudomonas strains having minimum inhibitory concentrations up to, or higher than, 100 Mg/ml require intravenous thbrapy to achieve such levels. No evidence of active metabolite formation has been obtained. Marked reductions in the half-life (and serum levels) of carbenicillin follow extracorporeal dialysis or peritoneal dialysis, the former producing the most striking effect [397]. These results were, of course, obtained in patients with severe renal failure. Patients with normal renal function rapidly eliminate the drug but, as with all penicillins, renal tubular secretion can be retarded by concurrent administration of probenecid. 

Some drugs, such as the two-substituted thiodiazole and acetazolamide (Diamox), increase serum uric acid by stimulating uric acid synthesis (K9). Others, such as chlorothiazide (Diuril), increase uric acid retention by decreasing uric acid excretion (K9). Hydrochlorothiazide inhibits tubular secretion and has been shown to increase pretreatment mean uric acid values from 6.5 mg/100 ml to 10.3 mg/100 ml by the third treatment day. In a patient with gout, the level increased from 8 mg/100 ml to 12 mg/100 ml (H6). In a single case a paradoxical hypouricemia occurred (H6). 

It does not inhibit cytochrome P450. Gatifloxacin is excreted as unchanged drug primarily by the kidney. Gatifloxacin undergoes glomerular filtration and tubular secretion. 

Any drug known to be largely excreted by the kidney that has a body half-life of less than 2 hours is probably eliminated, at least in part, by tubular secretion. Some drugs can be secreted and have long half-lives, however, because of extensive passive reabsorption in distal segments of the nephron (see Passive Diffusion, earlier in the chapter). Several pharmacologically active drugs, both anions and cations, known to be secreted are listed in Table 4.5. 

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... 

Nitrofurantoin is administered orally and is rapidly and almost completely absorbed from the small intestine only low levels of activity are achieved in serum because the drug is rapidly metabolized. Relatively high protein binding (about 70%) also affects serum levels, reducing potential for systemic toxicity and alteration of intestinal flora. Relative tissue penetration is much lower than other antimicrobials for UTIs, and therefore, nitrofurantoin is not indicated in the therapy of infections such as pyelonephritis and renal cortical or perinephric abscesses. Nitrofurantoin is rapidly excreted by glomerular filtration and tubular secretion to yield effective urinary levels. In moderate to severe renal dysfunction, toxic blood levels may occur while urinary levels may be inadequate. The drug is inactivated in the liver. 

Chloramphenicol is inactivated in the liver by glu-curonosyltransferase and is rapidly excreted (80-90% of dose) in the urine. About 5 to 10% of the administered drug is excreted unchanged. Renal elimination is by tubular secretion and glomerular filtration. Other degradation pathways are known to exist and may account for some of the toxicity seen in neonates and children. 

Cidofovir has extremely low oral bioavailability and so must be administered intravenously. Although the plasma elimination half-life averages 2.6 hours, the diphosphate form of the drug is retained within host cells and has an intracellular half life of 17 to 65 hours. A phosphocholine metabolite has a half-life of approximately 87 hours and may serve as an intracellular reservoir of the drug. Cidofovir is not significantly metabolized and is excreted unchanged by the kidney. Glomerular filtration and probenecid-sensitive tubular secretion are responsible for cidofovir elimination. 

CNS). Urinary excretion of unchanged drug is by renal tubular secretion. Dacarbazine metabolism and decomposition is complex. 

Methotrexate is well absorbed orally and at usual dosages is 50% bound to plasma proteins. The plasma decay that follows an intravenous injection is triphasic, with a distribution phase, an initial elimination phase, and a prolonged elimination phase. The last phase is thought to reflect slow release of methotrexate from tissues. The major routes of drug excretion are glomerular filtration andl active renal tubular secretion. 

Memantine is not a major substrate for hepatic cytochrome P450 isoenzymes and has not been shown to significantly inhibit or induce these enzymes. However, memantine is partially excreted by renal tubular secretion. Thus, concomitant use of other medications that use the same renal system (i.e., triampterene, hydrochlorothiazide, digoxin, cimetidine, ranitidine, metformin, and quinidine) may affect plasma levels of both drugs (Namenda 2005). Memantine should not be used in combination with other NMDA receptor antagonists, such as amantadine or dextromethorphan, because these combinations have not been formally studied. The clearance of memantine can be reduced when the urine is alkalinized, such as with the concomitant use of sodium bicarbonate or carbonic anhy-... 

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. 

Most of the drug is excreted unchanged by the kidney by tubular secretion and glomerular filtration.9-Carboxymethoxymethylguanine is the only significant metabolite of acyclovir recovered from the urine. 

Nitrofurantoin is well absorbed after ingestion. It is metabolized and excreted so rapidly that no systemic antibacterial action is achieved. The drug is excreted into the urine by both glomerular filtration and tubular secretion. With average daily doses, concentrations of 200 mcg/mL are reached in urine. In renal failure, urine levels are insufficient for antibacterial action, but high blood levels may cause toxicity. Nitrofurantoin is contraindicated in patients with significant renal insufficiency. 

Interference with renal excretion of drugs that undergo active tubular secretion, especially weak acids. Inhibition of glucuronide conjugation of other drugs. 

Interference with renal excretion of drugs that undergo active tubular secretion. Salicylate renal excretion dependent on urinary pH when large doses of salicylate used. Aspirin (but not other salicylates) interferes with platelet function. Large doses of salicylates have intrinsic hypoglycemic activity. 

Aspirin has been shown to slightly reduce the natriuretic effect of spironolactone in healthy individuals, possibly by reducing active renal tubular secretion of canrenone, the active metabolite of spironolactone. However, the hypotensive effect of spironolactone and its effect on urinary potassium excretion in hypertensive patients is apparently not affected. Until more clinical data are available on this potential interaction, patients receiving both drugs should be monitored for signs and symptoms of decreased clinical response to spironolactone [65]. 

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