Inhibition of flucloxacillin tubular renal secretion by piperacillin

To explore the extent, time course, site(s), mechanism and possible clinical relevance of the pharmacokinetic (PK) interaction between piperacillin and flucloxacillin.

A single-dose, randomized, six-way crossover study in 10 healthy volunteers where all subjects received all of the following as 5-min intravenous infusions: (i) 1.5 g piperacillin, (ii) 0.5 g flucloxacillin, (iii) 1.5 g piperacillin + 0.5 g flucloxacillin, (iv) 3 g piperacillin, (v) 1 g flucloxacillin, and (vi) 3 g piperacillin + 1 g flucloxacillin. Drug concentrations in plasma and urine were determined by high-performance liquid chromatography. WinNonlin was used for PK modelling and statistics.

Piperacillin significantly decreased the renal clearance of flucloxacillin from 5.44 to 2.29 l h(-1) (medians, P < 0.01) and the nonrenal clearance of flucloxacillin from 2.67 to 1.80 l h(-1) (P < 0.01). The renal clearance of flucloxacillin was reduced to 45% (point estimate, 90% confidence interval 40 to 50%) and the nonrenal clearance to 66% (59, 73). The extent of interaction was larger at the higher doses. Competitive inhibition of tubular secretion by piperacillin was identified as the most likely mechanism for the decreased renal clearance of flucloxacillin. Piperacillin had a 15-times higher affinity for the renal transporter than flucloxacillin based on the molar ratio. Piperacillin PK was only slightly affected by flucloxacillin.

Piperacillin inhibits renal and nonrenal elimination of flucloxacillin. This interaction seems clinically significant, as total clearance was reduced by a factor of 1.5 for the lower and 2.1 for the higher doses. PK interactions, especially with piperacillin, are likely to occur also with other beta-lactam combinations and might be useful to improve the effectiveness of antibacterial treatment.