Probenecid clearance

Probenecid is a uricosuric agent that blocks the tubular reabsorption of uric acid, increasing its excretion. Because of its mechanism of action, probenecid is contraindicated in patients with a history of uric acid stones or nephropathy. Probenecid loses its effectiveness as renal function declines and should be avoided when the creatinine clearance is 50 mL/minute or less. Its uricosuric effect is counteracted by low aspirin doses, which many patients receive for prophylaxis of coronary heart disease. 

Probenecid and sulfinpyrazone increase the renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid. They should only be... 

Penicillin or cephalosporin therapy The PSP excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about the normal rate when dosage of probenecid is adequate. 

Uricosurics like probenecid, sulfinpyrasone and benzbromaron increase urate clearance and fractional excretion of filtered urate. They are used in underexcretors of urate. Uricosurics benefit patients with hyperuricemia, intact renal function and no history of nephrolithiasis. In tropical and subtropical climates where most of the Third World countries are situated, the prevalence of urolithiasis is >40%. The use of uricosurics is contraindicated in patients with a history of urolithiasis as the number and size of stones will be increased. Without an history of urolithiasis, uricosurics still should be applied with caution where the risk for dehydration is high. 

The potential for drug interactions, particularly with other drugs that are actively secreted by the proximal tubules, should be considered. Probenecid has been shown to inhibit the renal clearance of acyclovir. Cyclosporine and other nephrotoxic agents may increase the risk of renal toxicity of acyclovir. 

Concurrent use of nephrotoxic agents may enhance the potential for nephrotoxicity. Probenecid and cimetidine decrease acyclovir clearance and increase exposure. Somnolence and lethargy may occur in patients receiving zidovudine and acyclovir. 

Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus infections. Intravenous cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein before each infusion, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended because of ocular toxicity. 

Indomethacin, introduced in 1963, is an indole derivative (Figure 36-1). It is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation. Probenecid prolongs indomethacin s half-life by inhibiting both renal and biliary clearance. 

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... 

Spahn H, Spahn I, Benet LZ. Probenecid-induced changes in the clearance of carprofen enantiomers a preliminary study. Clin Pharmacol Ther 1989 45(5) 500-505. 

Abemethy DR, Greenblatt DJ, Ameer B, et al. Probenecid impairment of acetaminophen and lorazepam clearance direct inhibition of ether glucuronide formation. J Pharmacol Exp Ther 1985 234(2) 345-349. 

Figure 8 Effect of probenecid on the plasma concentration of famotidine in healthy volunteers. Plasma concentration of famotidine was determined in healthy subjects treated with or without probenecid. The renal and tubular secretion clearances were decreased by the probenecid treatment (CLrenai 279 vs. 107 mL/min and CLsec 196 vs. 22 mL/min). Source (A) from Ref. 348 and (B) from Ref. 337.

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. 

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. 

Vree TB, van den Biggelaar-Martea M, Verwey-van Wissen CP. Probenecid inhibits the renal clearance of frusemide and its acyl glucuronide. Br J Clin Pharmacol 1995 39 692-695. 

Boom SP, Meyer I, Wouterse AC, et al. A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog. Biopharm Drug Dispos 1998 19 199-208. 

A number of drugs are known to inhibit the renal secretion of certain other drugs, resulting in decreased clearance of the latter. Examples of drugs decreasing the renal clearance of other drugs include probenecid, salicylates, sulfinpyrazone, phenylbutazone, and thiazide diuretics. As mentioned previously, the inhibition of penicillin secretion by probenecid due to competition between the two for renal tubule carriers is used therapeutically to increase penicillin blood levels. 

Second, certain nucleotide phosphonates (e.g., adefovir and cidofovir) are effective antivirals, but their use in the clinic is limited by renal toxicity. This is believed to be caused by avid uptake at the basolateral membrane of renal proximal tubule cells followed by slow transport into the urine at the apical membrane, a sequence of events that results in intracellular drug accumulation and thus toxicity. As with penicillin, the OAT family of transporters has been implicated in cidofovir uptake. Co-administration of probenecid with cidofovir has been shown to decrease renal clearance of the antiviral and reduce its nephrotoxicity, presumably through com-... 

Since penicillin is a substrate for the p-aminohippurate transporters, it is very rapidly cleared from the circulation. In the early days, when penicillin was very expensive, this rapid clearance was a major problem. The urine of patients receiving penicillin therapy was actually collected, and the secreted penicillin recovered. This problem was overcome by the development of probenecid (Figure 2.19b), which inhibits the second step in the above transport process.This results in a very pronounced prolongation of the retention of penicillin in the body. While no longer used routinely, probenecid is still used occasionally if high, stable plasma levels of penicillin are important in the treatment of life-threatening infections, such as brain abscesses. 

Valproate and probenecid may reduce clearance and raise plasma concentrations of lorazepam... 

CSF if the meninges are inflamed. Penicillins are organic acids and their rapid clearance from plasma is due to secretion into renal tubular fluid by the anion transport mechanism in the kidney. Renal clearance therefore greatly exceeds the glomerular filtration rate (127 ml/min). The excretion of penicillin can be usefully delayed by concurrently giving probenecid which competes successfully for the transport mechanism. Dosage of penicillins may should be reduced for patients with severely impaired renal function. 

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