Effects of probenecid on ketoprofen kinetics

Abstract

When six normal men took probenecid with ketoprofen in a two-treatment crossover study, steady-state plasma concentrations of ketoprofen and ketoprofen conjugates rose, but plasma protein binding of ketoprofen and urinary excretion of ketoprofen conjugates decreased. Probenecid decreased protein binding of ketoprofen by 28 +/- 7%, total ketoprofen clearance by 67 +/- 11%, clearance of unbound ketoprofen by 74 +/- 10%, clearance of unbound ketoprofen by conjugation by 91 +/- 5%, and renal clearance of ketoprofen conjugates by 93 +/- 4%. An apparent decrease (22 +/- 29%) in unbound ketoprofen clearance by mechanisms other than conjugation might have been established in a study of more than six subjects. Probenecid, which reaches plasma concentrations that approach 100 times those of ketoprofen or its conjugates, appears to inhibit both the conjugation of ketoprofen and the renal excretion of ketoprofen conjugates. An alternative explanation to inhibition of conjugation involves cumulation and subsequent hydrolysis of ketoprofen conjugates as a result of the renal action of probenecid. In addition to the advantages of obtaining simultaneous uricosuric and anti-inflammatory effects, there may be clinical kinetic advantages of administration of probenecid with ketoprofen, because the large interdose concentration swings of ketoprofen are then substantially reduced.

Naproxen pharmacokinetics in the elderly.

“…It should be further noted that generally held conceptions of the apparent volume of distribution and clearance (total and unbound) pertain to situations where elimination occurs from the pharmacokinetic compartment into which the dose was loaded. This principle would be contravened by the mechanism described above in which naproxen conjugates can regenerate naproxen; naproxen conjugates in plasma constitute a peripheral (chemical) compartment which is in equilibrium with the dosed and sampled compartment (naproxen in plasma) but from which elimination takes place in the form of urinary excretion of naproxen conjugates (Upton et al, 1982).…”

“…In Anttila's renal patients at least, a concomitant loss of hepatic function is possible -in that study, renal failure patients were also on average 22 years older than normal subjects. A mechanism likely to account in large part for the apparent loss of intrinsic clearance of naproxen with loss of renal function is the impairment of urinary excretion of ester conjugates of naproxen which normally account for 60% of the dose but which are readily hydrolyzable in vivo to regenerate naproxen per se (Gugler, 1978;Upton et al, 1980bUpton et al, , 1982.…”

“…Because of the nature of naproxen metabolism, with a potential for reversible metabolism via a labile renallyeliminated conjugate (Gugler, 1978;Upton et al, 1982), it may be difficult to resolve correctly the effects of diminished hepatic and renal function. Naproxen in plasma is almost completely bound to protein but the degree of this binding is dependent upon the naproxen concentration (Held, 1980).…”

Reduced elimination of ketoprofen in the elderly is not necessarily due to impaired glucuronidation.

“…Ester glucuronides are susceptible to hydrolysis in biological fluids in vitro (Rubin et al, 1972;Faed & McQueen, 1979;Upton et al, 1980) (Verbeeck, 1982). Coadministration of probenecid also leads to a reduced elimination of ketoprofen, clofibric acid and diflunisal (Upton et al, 1982;Veenendaal et al, 1981;Meffin et al, 1981). Probenecid itself undergoes glucuronoconjugation and therefore may reduce the elimination of these three drugs by inhibition of the glucuronidation pathway.…”

The influence of renal function on the enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in patients with rheumatoid arthritis.

“…A low percentage of the dose of such drugs is cleared renally in unchanged form yet, paradoxically, a number of them have diminished clearance in patients with renal dysfunction, or in elderly patients in whom renal function is reduced [8][9][10][11][12][13][14]. Moreover, coadministration of probenecid has caused a decrease in the plasma clearance of these NSAIDs [15][16][17][18][19]. It has been suggested by Meffin [20], from mechanistic studies in animals [21,22], that such observations are consistent with a decrease in the renal elimination of acylglucuronides leading to persistence of these labile metabolites in the body followed by their systemic hydrolysis back to the parent aglycone.…”