BILIARY ELIMINATION AND HEPATIC DISPOSITION OF AN ASSOCIATION OF PIPERACILLIN AND TAZOBACTAM - EXPERIMENTAL EVALUATION

Biliary elimination and hepatic disposition of tazocillin, an associat ion of a highly bile-excreted ureido-penicillin, piperacillin, with a beta-lactamase inhibitor, tazobactam, have been assessed applying an i solated perfused rabbit liver experimental model. Six investigations w ere performed, each during a 3h period, using reconstituted blood circ ulating in a closed circuit. Piperacillin and tazobactam concentration in all specimens were determined by high performance liquid chromatog raphy. Blood samples and cumulative bile secretion were collected ever y 30 min, and liver fragments were isolated at the end of each experim ent for dosage purposes. Following the simultaneous administration of piperacillin 80 mg and tazobactam 10 mg (dose ratio 8/1) in the perfus ion device, theoretical initial serum concentrations were respectively 414 mu g/ml and 32.1 mu g/ml. Maximal biliary concentrations of 4431 +/- 1541 (s.d.) of piperacillin and 21.3 +/- 7.8 mu g/ml of tazobactam were reached between 0.5-1h and 2.5-3h, respectively. Cumulative bili ary excretion (0-3h) amounted to 37.6 +/- 17.7% of the administered do se for piperacillin and 1.5% for tazobactam At the end of the perfusio n, respectively 22.1% and 50.7% of piperacillin and tazobactam doses r emained in the circulating blood, while 1.1% and 5.6% were found in th e liver. On the basis of these data, the calculated percentages of pip eracillin and tazobactam doses having undergone hepatic biotransformat ion, were 6.5% and 1.2%, respectively. Under such experimental conditi ons, concentrations and excretion of piperacillin in bile prove to be substantial. Of note, tazobactam concentrations turn out to be stable both in serum and in bile whereas they stay at a relatively constant l evel of 20 mu g/ml during nearly all the perfusion time. These results are compared with experimental data concerning 20 other beta-lactam a ntibiotics and beta-lactamase inhibitors studied under the same condit ions. The values presented show that the biliary elimination of pipera cillin and tazobactam should enable tazocillin to exhibit high and sus tained antibacterial activity in the biliary tract. To what extent the se data might be extrapolated to humans remains to be specified.