Cephalosporin-Probenecid Drug Interactions

Abstract

The effect of concurrent probenecid administration on the pharmacokinetics of cephalosporin antibiotics varies with the available cephalosporins. Most cephalosporins are affected to some degree by concurrent probenecid administration, although ceforanide, ceftazidime, ceftriaxone and latamoxef (moxalactam) have no significant changes in pharmacokinetics. For those cephalosporins affected by probenecid, the predominant findings are impairment in renal clearance resulting in increased peak serum concentrations, an increased area under the concentration-time curve (AUC), and both delayed and prolonged recovery of the cephalosporin in the urine. The distribution of the cephalosporins is affected to varying degrees, with reports of increased penetration into ocular, central nervous system and blister fluids noted with some agents. The clinical relevance of the changes in cephalosporin distribution associated with probenecid administration has not been investigated. The dose and timing of probenecid administration appear to be major determinants in any possible interaction. Studies with ceftizoxime and cefoxitin suggest that larger probenecid doses result in greater changes in the pharmacokinetics of cephalosporins. Prolonged probenecid therapy before administration of a cephalosporin did not seem to be as relevant as the probenecid dosage in determining the magnitude of the interaction. Probenecid administration with or immediately before cephalosporin administration appears able to produce these documented changes in cephalosporin pharmacokinetics. The route of administration (oral versus parenteral) of either prolosporin pharmacokinetics. The route of administration (oral versus parenteral) of either probenecid or the cephalosporin does not appear to influence the characteristics of the interactions. The therapeutic efficacy of a combination of a cephalosporin with probenecid has been most thoroughly studied for single-dose treatment of gonorrhoea. The addition of probenecid to cephalosporin therapy results in sustained systemic concentrations adequate for eradication of Neisseria gonorrhoeae. Regimens involving either second or third generation cephalosporins demonstrate good success rates with single-dose therapy. However, the success of ceftriaxone administered alone for treatment of both penicillase-producing and non-penicillase-producing strains of N. gonorrhoeae suggests that the addition of probenecid is unnecessary. The use of probenecid, in combination with cephalosporins, to enhance the treatment of other venereal and systemic infections has preliminary, inconclusive support.

Effects of Organic Anion, Organic Cation, and Dipeptide Transport Inhibitors on Cefdinir in the Isolated Perfused Rat Kidney

“…In that study, the CL R s were 2.78, 2.14, 2.10, and 1.97 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 for 200-, 300-, 400-, and 600-mg doses, respectively. This observation is consistent with previous reports that ␤-lactam drugs are eliminated by glomerular filtration, as well as anionic and cationic carrier-mediated secretory systems, in the kidney (5,40). Furthermore, it has been shown in vitro that some dicarboxylic, ␣-amino, and non-␣-amino ␤-lactams, including cefdinir, can be recognized by the carrier-mediated dipeptide transporters PEPT1 and PEPT2 (12,36,37).…”

Organic Anion Transporters and Their Implications in Pharmacotherapy

“…A similar example of such a drug-drug interaction is that of probenecid and the diuretic furosemide, although OAT3 has a higher affinity for furosemide, it is also very likely that probenecid interacts with other loop and thiazide diuretics that are more specific substrates of OAT1 and decreases their renal excretion. Finally, as mentioned above, probenecid may prevent kidney damage of antivirals by reducing renal accumulation; therefore, cytotoxicity of these compounds (Brown, 1993;Cihlar et al, 1999;Uwai et al, 2000).…”

“…A classic example of drug-drug interaction involves the uricosuric drug probenecid and penicillin, which results in a decreased renal excretion of penicillin in patients. Although it is now believed that OAT3 is the main transporter responsible for the excretion of penicillin, the same principle applies to the renal excretion of various cephalosporins, which are primarily believed to be transported by OAT1 (Tsuji et al, 1990;Brown, 1993). A similar example of such a drug-drug interaction is that of probenecid and the diuretic furosemide, although OAT3 has a higher affinity for furosemide, it is also very likely that probenecid interacts with other loop and thiazide diuretics that are more specific substrates of OAT1 and decreases their renal excretion.…”

Impact of Genetic Knockout of PEPT2 on Cefadroxil Pharmacokinetics, Renal Tubular Reabsorption, and Brain Penetration in Mice

“…The renal secretion of most cephalosporins is believed to be mediated by organic anion transporters (OATs) located on the basolateral membrane of proximal tubule epithelia Shitara et al, 2005). Thus, the elimination rate of cefadroxil (and similar compounds) is significantly reduced by coadministration of probenecid, an inhibitor of OAT (Brown, 1993;Shitara et al, 2005). However, some cephalosporins are also subjected to renal reabsorption since they are substrates of PEPT1 and PEPT2 (Ganapathy et al, 1995), which are localized on the brush-border membrane of the proximal tubule.…”