Effect of probenecid on the elimination and protein binding of ceftriaxone

Summary The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d.Probenecid increased the total systemic clearance (CL_S^T) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t_1/2()^T) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CL_R^F) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone.The final value of CL_R^F was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CL_NR^F) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CL_S^F) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg).As a consequence of a decreased affinity constant (K_A), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid.The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.Abbreviations AUC^T, AUC^F plasma AUC of total and free (unbound) drug - CL_S^T, CL_S^F clearance: total systemic, free systemic - CL_O^T, CL_R^F total oral, free renal - CL_NR^F free non-renal - V_Z^TV_SS^T apparent volume of distribution: terminal phase, total drug; corrected steady-state, total drug [14] - f average free fraction of drug in plasma - f_e fraction of dose excreted unchanged in urine - t_1/2()^T terminal t_1/2: total drug - t_1/2()^F free drug - K_A affinity constant - nP capacity constant - C_av^ss steady-state concentration in plasma during multiple dosing - C_B bound concentration - C_F free (unbound) concentration