Objectives: We evaluated the effects of probenecid on the Pharmaco Kinetics (PK) and pharmacodynamics (PD) of oral cephalexin in healthy volunteers.

Methods: Cephalexin 1000 mg was administered orally to 11 healthy volunteers following a standardized meal, with and without probenecid 500 mg orally, on two separate days one week apart. Total plasma concentrations of cephalexin and probenecid over a 12 h period were measured by liquid chromatography tandem mass spectrometry. Standard pharmacokinetic measures and contemporary PK/PD targets were compared.

Results: Probenecid increased the mean (95% CI) cephalexin area under the concentration-time curve (AUC_0-∞) 1.73-fold (1.61–1.85, p < 0.0001), peak concentration 1.37-fold (1.16–1.58, p < 0.01), time to peak concentration 1.45-fold (1.1–1.8, p < 0.01)_, and half-life 1.33-fold (1.03–1.62, p < 0.05). The effects resulted in clinically meaningful increases in the probability of PK/PD target attainment (PTA). As an example, the PTA of total concentrations above the minimum inhibitory concentration required to inhibit methicillin-susceptible Staphylococcus aureus isolates (MIC ≤ 8 mg/L) for 70% of a 6 h dose interval approached 100% for cephalexin + probenecid while for cephalexin alone it was <15%.

Conclusions: Probenecid prolonged and flattened the plasma concentration-time curve, enhancing the probability of attaining PK/PD targets. Co-administration of probenecid may expand the clinical benefits of oral cephalexin.