Renal tubular secretion

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. 

Abbreviations GER. gastric-emptying rate Vj, volume of distribution /, 2r half-life GFR, glomerular filtration rate ARTS active renal tubular secretion. 

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. 

In rats ammonium perfluorooctanoate induced hepatomegaly that was more pronounced in the male than in the female. Male rats are thought to be more sensitive to the toxic effects of ammonium perfluorooctanoate because of their slower excretion rate. The rapid excretion by female rats is due to active renal tubular secretion, which is considered to be hormonally controlled by estradiol and testosterone levels. The hepatomegaly was hypertrophic rather than hyperplastic and involved proliferation of peroxisomes. 

Excretion - Penicillins are excreted largely unchanged in the urine by glomerular filtration and active tubular secretion. Nonrenal elimination includes hepatic inactivation and excretion in bile this is only a minor route for all penicillins except nafcillin and oxacillin. Excretion by renal tubular secretion can be delayed by coadministration of probenecid. Elimination half-life of most penicillins is short (no... 

The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme could occur. Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir. Drug/Food interactions When famciclovir was administered with food, penciclovir Cmax decreased approximately 50%. Because the systemic availability of penciclovir (AUC) was not altered, it appears that famciclovir may be taken without regard to meals. 

Natiuretic response to diuretics including fruse-mide and bumetanide is reduced as a result of decreased renal tubular secretion of diuretic Thus, age-related changes in renal tubular function may influence not only pharmacokinetics but also drug action on the kidney (pharmacodynamics). 

Urinary excretion is the major elimination path for most cephalosporins. When prescribing cephalosporins to patients with renal failure, practitioners must consider dose reduction or dose interval extension (Table 45.2). Renal tubular secretion contributes to the elimination of some cephalosporins, and an increase in cephalosporin plasma concentrations may occur when probenecid blocks renal tubular secretion of cephalosporins. Biliary elimination is important for some cephalosporins. Cefmetazole, cefoperazone (Cefobid), cefoxitin, and ceftriaxone achieve biliary concentrations greater than those in plasma. After parenteral administration of cefoperazone, 70% of the dose appears in the bile within 24 hours. Practitioners should decrease the dose of cefoperazone when prescribing for patients with hepatic failure or biliary obstruction. Metabolism is not a major elimination path for most cephalosporins. Cefotaxime is one of the few cephalosporins having an active metabolite, desacetyl cefotaxime. 

Famciclovir may interact with probenecid or other drugs eliminated by renal tubular secretion. This interaction may result in increased blood levels of penciclovir or other agents. 

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. 

Salicylates, probenecid, and sulfonamides inhibit the renal tubular secretion of methotrexate and may displace it from plasma proteins. Asparaginase inhibits protein synthesis and may protect cells from methotrexate cytotoxicity by delaying progression from Gj-phase to S-phase. Methotrexate may either enhance or inhibit the action of fluorouracil, depending on its sequence of administration. 

Mechanism of Action An antigout agent that competitively inhibits reabsorption of uric acid at the proximal convoluted tubule. Also, inhibits renal tubular secretion of weak organic acids, such as penicillins. Therapeutic Effect Promotes uric acid excretion, reduces serum uric acid level, and increases plasma levels of penicillins and cephalosporins. 

Plasma protein binding generally limits renal tubular secretion and biotransformation... 

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-... 

All thiazides and related compounds are well absorbed from the GIT and begin to produce diuresis within one hour after oral administration, but the duration is variable, which are due to variation in rates of renal tubular secretion and clearance, metabolism, and enterohepatic circulation. Approximately 50 percent of an oral dose is excreted in urine within 6 hours. Most of the agents undergo little hepatic metabolism and excreted as such. However indapamide is extensively metabolized. 

Except for oral amoxicillin, penicillins should be given 1-2 hours before or after a meal they should not be given with food to minimize binding to food proteins and acid inactivation. Blood levels of all penicillins can be raised by simultaneous administration of probenecid, 0.5 g (10 mg/kg in children) every 6 hours orally, which impairs renal tubular secretion of weak acids such as 3-lactam compounds. 

Although the terminal half-life of cidofovir is 2.6 hours, the active metabolite, cidofovir diphosphate, has a prolonged intracellular half-life of 17-65 hours, thus allowing infrequent dosing. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Cerebrospinal fluid penetration is poor. Elimination is by active renal tubular secretion. High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%. 

H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels. 

Inhibits hepatic microsomal drug-metabolizing enzymes. (Ranitidine, famotidine, and nizatidine do not.) May inhibit the renal tubular secretion of weak bases. 

Drugs that impair renal tubular secretions (aminoglycosides, amphotericin B)... 

In a double-blind, randomized, crossover study in 12 healthy volunteers, cefalexin 500 mg increased the Cmax and AUC of a single dose of metformin 500 mg by 34 and 24% respectively and reduced its renal clearance to 14% (138). The authors suggested that cefalexin inhibits the renal tubular secretion of metformin. 

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,... 

Inhibits hepatic microsomal drug-metabolizing enzymes. (Ranitidine, famotidine, and nizatidine do not appear to do so.) May inhibit the renal tubular secretion of weak bases. Purportedly reduces hepatic blood flow, thus reducing first-pass metabolism of highly extracted drugs. (However, the ability of cimetidine to affect hepatic blood... 

Anaizi NH, Cohen JJ. 1978. The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the renal tubular secretion of phenolsulfonphthalein. J Pharmacol Exp Ther 207 748-755. 

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]. 

The interaction between ZDV and probenecid has been extensively studied in vitro and in several species. The interaction is complex. Probenecid inhibits the renal tubular secretion of both ZDV and ZDV glucuronide. Probenecid also directly affects the glucuronidation step, thus decreasing the nonrenal clearance of ZDV. For example, the nonrenal clearance of ZDV was significantly... 

Hori R, Okamura N, Aiba T, et al. Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. J Pharmacol Exp Ther 1993 266 1620-1625. 

Odlind B, Beermann B, Lindstrom B. Coupling between renal tubular secretion and effect of bumetanide. Clin Pharmacol Ther 1983 34 805-809. 

Williams WM, Chen TS, Huang KC. Effect of penicillin on the renal tubular secretion of methotrexate in the monkey. Cancer Res 1984 44 1913-1917. 

The ratio of renal clearance of digoxin to creatinine clearance decreased with the coadministration of clarithromycin (0.64 and 0.73), and was restored (1.30) after administration of clarithromycin had stopped (326). The role of P-gp efflux in this interaction was confirmed using an in vitro kidney epithelial cell line (326). The administration of itraconazole, a P-gp inhibitor, with digoxin resulted in an increased trough concentration and a decrease in the amount of renal clearance, possibly by an inhibition of the renal tubular secretion of digoxin via P-gp (329). The P-gp modulator verapamil has also been shown to decrease the renal clearance of digoxin (330). 

Ito S, Woodland C, Harper PA, et al. P-glycoprotein-mediated renal tubular secretion of digoxin the toxicological significance of the urine-blood barrier model. Life Sci 1993 53(2) L25-L31. 

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