Probenecid Oseltamivir

Probenecid Coadministration of probenecid results in an approximate 2-fold increase in exposure to oseltamivir carboxylate because of a decrease in active anionic tubular secretion in the kidney. 

No formal drug interaction studies of oseltamivir have been performed. Oseltamivir and its carboxylate metabolite do not interact with the cytochrome P450 system. Although probenecid decreases the elimination of oseltamivir, dosage adjustment is not required during coadministration of these drugs because of oseltamivir s margin of safety. Oseltamivir does not interfere with antibody production in response to the influenza vaccine. 

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. 

In healthy subjects probenecid completely blocked the renal secretion of the active metabolite of oseltamivir after oral administration, increasing its AUC 2.5 times (20). In vitro studies of the metabolite on the human renal organic anionic transporter I (hOATl) were investigated in Chinese hamster ovary cells stably transfected with the transporter. The metabolite was a low-efficiency substrate for hOATl and a very weak inhibitor of hOATl-mediated transport of pora-aminohippuric acid. Probenecid inhibited the transport of the metabolite, pora-aminohippuric acid, and amoxicillin via hOATl. 

Oral oseltamivir phosphate is absorbed rapidly and cleaved by esterases in the GI tract and liver to the active carboxylate. Low levels of the phosphate are detectable, but exposure is only 3 to 5% of that of the metabolite. The bioavailability of the carboxylate is estimated to be approximately 80%. The time to maximum plasma concentrations of the carboxylate is about 2.5 to 5 hours. Food does not decrease bioavailability but produces the risk of GI intolerance. After 75-mg doses, peak plasma concentrations average 0.07 pg/mL for oseltamivir phosphate and 0.35 pg/mL for the carboxylate. The carboxylate has a volume of disttibution similar to extracellular water. Broncho-alveolar lavage levels in animals and middle-ear fluid and sinus concentrations in humans are comparable with plasma levels. Following oral administtation, the plasma half-life of oseltamivir phosphate is 1 to 3 hours and that of the carboxylate ranges from 6 to 10 hours. Both the prodrug and active metabolite are eliminated primarily unchanged through the kidney. Probenecid doubles the plasma half-life of the carboxylate, which indicates tubular secretion by the anionic pathway. 

Probenecid inhibits the renal secretion of the active metabolite of oseltamivir and marked raises its plasma levels, but this is not clinically relevant because of the wide safety margin of oseltamivir. There was no pharmacokinetic interaction between amoxicillin and oseltamivir, and cimetidine did not alter oseltamivir pharmacokinetics. 

In a crossover study in 18 healthy subjects probenecid 500 mg every 6 hours for 4 days approximately halved the renal clearance of the active metabolite of oseltamivir, and increased its AUC by about 2.5-fold when a single 150-mg dose of oseltamivir was given on day 2. ... 

Probenecid appears to completely inhibit the renal tubular secretion of the active metabolite of oseltamivir via the anionic renal transporter process. Oseltamivir does not alter amoxicillin pharmacokinetics, suggesting minimal potential to inhibit the renal anionic transport process. Cimetidine, which inhibits the renal tubular secretion of drugs via the cationic secretion transport process, had no effect on oseltamivir. 

Probenecid markedly increased the AUC of the active metabolite of oseltamivir, but because of the large safety margin of oseltamivir, this increase is not considered to be clinically relevant. " Oseltamivir did not alter amoxicillin pharmacokinetics, and is therefore unlikely to interact with other renally secreted organic acids. Other drugs that are involved in the active anionic tubular secretion mechanism are also unlikely to interact. Cimetidine does not interact with oseltamivir, and other drugs that are inhibitors of the renal cationic secretion transport process are unlikely to interact. ... 

Drug-drug interactions Probenecid In a three-arm, open study 48 healthy volunteers were randomized to oral oseltamivir 75 mg/ day, oseltamivir 75 mg every 48 hours -I- probenecid 500 mg qds, or oseltamivir 75 mg every 48 hours + probenecid 500 mg bd for 15 days. Probenecid reduced the systemic availability of oseltamivir by about 30% and the steady-state apparent oral clearance by about 25% [264 ]. The authors noted that alternate-day dosing of oseltamivir plus probenecid four times a day achieved trough... 

The effects of probenecid on the pharmacokinetics of four doses of oseltamivir have been studied in healthy Thai adults [265. The median half-lives were 1.0 hour for oseltamivir and 5.1 hours for oseltamivir carbox-ylate. In one subject there was markedly reduced hydrolysis of oseltamivir to its car-boxylate, consistent with impaired carboxylesterase activity. Co-administration of probenecid resulted in a mean 40% reduction in the apparent volume of distribution of oseltamivir carboxylate and a 61% reduction in its renal ehmination, with a consequent 154% increase in the AUC. The AUC increase in saliva was about three times less than the AUC increase in plasma. The authors concluded that probenecid coadministration may reduce oseltamivir dose requirements considerably. 

However, there is also evidence that adverse reactions may be more common when this combination is used. During a pharmacokinetic study in healthy volunteers a 68-year-old woman developed severe thrombocytopenia after taking the combination, and no other drug therapy, for 2 weeks [266 j. Her platelet count fell from 200 to 15 X 10 /1. The two drugs were discontinued and her platelet count returned to normal within 1 week. In a review of the FDA s Adverse Event Reporting System database there were 93 cases of reduced platelet counts associated with oseltamivir and 24 associated with probenecid. Signal detection analyses were significant for oseltamivir but not probenecid. 

Raisch DW, Cunningham F, Lin ET, Olivo N, Deyton LR. Pharmacokinetics and tolerability of oseltamivir combined with probenecid. Antimicrob Agents Che-mother 2008 52(9) 3013-21. 

Raisch DW, Straight TM, Holodniy M. Thrombocytopenia from combination treatment with oseltamivir and probenecid case report, MedWatch data summary, and review of the literature. Pharmacotherapy 2009 29(8) 988-92. 

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