Naproxen‐probenecid interaction

Abstract

Probenecid induced major alterations in the half-life. renal clearance, and metabolism of naproxen. In 6 healthy subjects who received 500-mg single oral doses of naproxen alone and (following two days of probenecid loading) with 500 mg of probenecid 4 times a day, there was an increase in naproxen plasma half-life from the normal 14 to 37 hr. Twenty-jour hour naproxen plasma levels were doubled by probenecid. but the rate and extent of absorption were not affected. In an 8-day chronic administration experiment (250 mg twice daily). naproxen steady-state plasma levels measured before the morning dose were increased 50% by coadministration of 500 mg probenecid twice daily. The major probenecid effects on naproxen metabolism were a 66% reduction of the naproxen conjugates excreted in the urine and an increase in urinary 6-0-desmethyl naproxen. The renal clearance of unchanged naproxen was markedly depressed. We conclude that probenecid retards naproxen plasma clearance by inhibiting naproxen glucuronide formation and renal clearance of naproxen. The renal clearance effect is the result of the blocking of tubular secretion of organic anions by probenecid. Inhibition of conjugate formation by probenecid may be the result of successful competition for conjugative processes since a large percentage of both drugs are cleared from the plasma by conjugation. Because of this interaction, patients who receive naproxen and probenecid in combination will have higher steady-state plasma levels of naproxen and form more of the 6-0-desmethyl metabolite than when probenecid is not used.

Renal elimination of the hypoxic cell radiosensitizer misonidazole in wistar rats: influence of some drugs on its excretion

“…We think that a same process is involved for Miso. On the other hand, Runkel et al, (14) suggest that probenecid inhibits the glucuroconjugation of naproxen. We observe the same phenomenon in the case of the interaction Misoprobenecid.…”

Adverse Drug Interactions with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

“…Since glucuronidation accounts for such a small fraction ofthe total metabolism, it is unlikely that interactions involving probenecid and indomethacin glucuronide metabolite formation or clearance could be entirely responsible for a significant rise in indomethacin plasma concentrations. Similarly, it is unlikely that probenecid interacts with indomethacin primarily by inhibiting the renal clearance of unchanged drug since only 10 to 20% of indomethacin is excreted unchanged (Runkel et al 1978). At the present time the probenecid-indomethacin interaction requires further elucidation.…”

“…Coadministration of probenecid with NSAIDs may occur during the treatment of acute gout (Tonkin & Wing 1988). Probenecid has been reported to increase markedly the plasma concentrations of indomethacin (Baber et al 1978;Skeith et al 1968), naproxen (Runkel et al 1978 - fig. 6), diflunisal (Meffin et al 1981), ketoprofen (Upton et al 1982) and carprofen (Spahn et al 1989;Yu & Perel 1980).…”

The pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans. Effect of cimetidine.

“…Descriptions of the pharmacokinetics of naproxen have been based on fluorimetric measurement of total naproxen concentration in plasma and urine after hydrolysis of the conjugates (Anttila, 1977;Anttila et al, 1980;Mortensen et al, 1979), g.l.c. (Runkel et al, 1972a(Runkel et al, ,b, 1973(Runkel et al, , 1974(Runkel et al, , 1976(Runkel et al, , 1978Weber et al, 1981), t.l.c. (Abdel-Moety et al, 1988) and mass fragmentography (G0tzsche et al, 1983;Larssen & Marinelli, 1981).…”