Probenecid renal elimination

Combination with probenecid. Renal elimination of penicillin occurs chiefly via the anion (acid)-secretory system of the proximal tubule (-COOH of 6-APA). The acid probenecid (p. 316) competes for this route and thus retards penicillin eUmination ... 

Penicillin G is excreted by the kidneys, with 90% of renal elimination occurring via tubular secretion and 10% by glomerular filtration. Probenecid blocks tubular secretion and has been used to increase the serum concentration and prolong the half-life of penicillin G and other penicillins. Additional pharmacokinetic information can be found in Table 45.1. 

Probenecid APAP Renal elimination of glucronide decreased from 260 to 84 mg/day 146... 

Probenecid has been reported to inhibit renal elimination of many drugs acyclovir (325,326), allopurinol (327), bumetanide (328), cephalosporins (329-334), cidofovir (335), ciprofloxacin (336), famotidine (337), fexofenadine (338), furosemide (339), and oseltamivir (Ro 64-0802) (340). Recent studies have elucidated that probenecid is a potent inhibitor of renal organic anion transporters (OAT1 and OAT3) with the Ki values lower than the unbound plasma concentration of probenecid, indicating the interaction with probenecid includes inhibition of the basolateral uptake process mediated by OAT1 and/or OAT3. 

OCT2 to the tubular secretion of cimetidine and famotidine. Furthermore, a great interspecies difference was found in the effect of probenecid, which had no effect on the tubular secretion of famotidine and cimetidine in rats (Fig. 8) (348). Two factors have been proposed for this interspecies difference (1) expression of Octl only in rodent kidney and (2) greater transport activity of famotidine by OAT3 than by Oat3 (120). In monkey, as in the case in human, probenecid had significant effect on the renal elimination of famotidine, but not for cimetidine (152). 

Renal clearance accounts for 61% of the total body clearance of ciprofloxacin in humans (350). Coadministration of probenecid reduces the total body and renal clearance to 59% and 36% of the control value, respectively, but has no effect on the nonrenal clearance (336). The transporters involved in the renal elimination of ciprofloxacin remains unknown. 

Tahara H, Kusuhara H, Chida M, et al. Is the monkey an appropriate animal model to examine drug-drug interactions involving renal clearance Effect of probenecid on the renal elimination of H2 receptor antagonists. J Pharmacol Exp Ther 2006 316 1187-1194. 

Gisclon LG, Boyd RA, Williams RL, et al. The effect of probenecid on the renal elimination of cimetidine. Clin Pharmacol Ther 1989 45 444-452. 

METHOTREXATE ANTIGOUT DRUGS -PROBENECID t methotrexate levels Probenecid 1 elimination of methotrexate renally by interfering with tubular secretion in the proximal tubule and also 1 protein binding of methotrexate (a relatively minor effect). Probenecid competes with methotrexate for renal elimination Avoid co-administration if possible if not possible, 1 dose of methotrexate and monitor FBC closely... 

Renal elimination is by glomerular filtration and active tubular secretion, which can be blocked by probenecid. As noted in Table 2, urinary recovery of the quinolones is variable. The antibacterial activity of these compounds is reduced at low urinary pH [215]. 

Agents used to treat acute gout attacks as well as to prevent recurrent attacks should be used with caution in patients with hypertension and renal impairment. Doses may need to be adjusted in patients with decreased renal function. Probenecid is usually recommended for patients who are under 60 years of age, who have normal renal function, are diagnosed as an underexcreter, and have no history of kidney stones. Probenecid causes a marked increase of uric acid in the urine, and decreased renal elimination places the patient at risk for stone formation. Allopurinol is a good choice for patients with uric acid stones or renal insufficiency, as well as for those who are known to be overproducers of uric acid. 

In one study, probenecid 1 g, given 30 minutes before ciprofloxacin 500 mg, was found to reduce the renal clearance of ciprofloxacin by up to 50%. Other pharmacokinetic parameters (maximum serum levels, AUC) were unchanged and no accumulation of ciprofloxacin appeared to occur, probably due to an increase in extra-renal elimination. ... 

The likely explanation for this interaction is that probenecid successfully competes with some quinolones for tubular excretion, so that their renal elimination is reduced. Some quinolones are more dependent on glomerular filtration (e.g. grepafloxacin) than tubular excretion for elimination, and thus are unaffected by competition for tubular excretion. ... 

It was suggested that cidofovir/probenecid might alter the renal elimination of these drugs. ... 

A study in 10 HIV-positive patients found that probeneeid 1 g twiee daily for 3 days had no effeet on the pharmaeokineties of fosearnet 90 mg/kg given intravenously over 2 hours. The authors eonelude that, beeause of the lack of interaction with probenecid, almost all of the renal elimination of foscarnet is by glomerular filtration, with only a minimal contribution of active tubular secretion. No special precautions seem to be necessary. 

From the above account, it is evident that the therapeutic range of the original penicillin G has been considerably extended through the new semi-synthetic products. These are, however, more costly, and should not be prescribed without good reason. An economy can be effected, when giving a member of the amoxycillin family orally, by prescribing oral probenecid 3.16) as well, because this decreases renal elimination of penicillins. 

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. 

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. 

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. 

The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular filtration and tubular secretion. Absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2-3 hours) and is nearly as complete as with intravenous administration. The duration of effect for furosemide is usually 2-3 hours and that of torsemide is 4-6 hours. Half-life depends on renal function. Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion by the proximal tubule. Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule. Metabolites of ethacrynic acid and furosemide have been identified, but it is not known if they have any diuretic activity. Torsemide has at least one active metabolite with a half-life considerably longer than that of the parent compound. 

Although the terminal half-life of cidofovir is about 2.6 hours, the active metabolite, cidofovir diphosphate, has a prolonged intracellular half-life of 17-65 hours, thus allowing widely spaced administration. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Peak serum concentrations when administered with probenecid (see Clinical Uses) are about 19 g/mL. Cerebrospinal fluid penetration is poor after intravenous administration. Elimination involves active renal tubular secretion. High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%. 

Benzylpenicillin disappears from the blood very rapidly (the elimination half-life is 30 minute in the adult), and 60-90% of dose is excreted in the urine (350). The renal clearance is approximately equal to the blood flow rate, indicating a high secretion clearance (350). Probenecid and phenylbutazone reduced its renal clearance to 60%, while sulfinpyrazone reduced it to 40% of the control value (351). In rat kidney, Oat3 has been suggested to be responsible for the uptake of benzylpenicillin (53). As discussed above, inhibition of uptake process mediated by OAT3 is likely mechanics underlying this interaction. 

Excretion The primary route of excretion is through the organic acid (tubular) secretory system of the kidney (see p. 224), as well as by glomerular filtration. Patients with impaired renal function must have dosage regimens adjusted. Thus the Xyz of penicillin G can increase from a normal of 1/2 -1 hour to 10 hours in individuals with renal failure. Probenecid inhibits the secretion of penicillins. Nafcillin is primarily eliminated through the biliary route. [Note This is also the preferential route for the acylureido penicillins in cases of renal failure.]... 

Uricosurics, such as probenecid or benz-bromarone (100 mg/day), promote renal excretion of uric acid. They saturate the organic acid transport system in the proximal renal tubules, making it unavailable for urate reabsorption. When underdosed, they inhibit only the acid secretory system, which has a smaller transport capacity. Urate elimination is then inhibited and a gout attack is possible. In patients with urate stones in the urinary tract, uricosurics are contraindicated. 

Inhibition of transport processes that carry substances across cells, e.g. blockade of anion transport in the renal tubule cell by probenecid can be used to delay excretion of penicillin, and to enhance elimination of mate... 

The elimination of renally excreted sulphonylureas (e.g. carbutamide, chlorpropamide, glisoxepide) may be diminished by probenecide and salicylates. 

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