Biliary elimination of ticarcillin plus clavulanic acid (Claventin): experimental and clinical study

The aim of the present study was to assess the biliary elimination and disposition of Claventin, a combination of clavulanic acid (CA), a beta-lactamase inhibitor, with ticarcillin (TIC), resulting in an enhancement of the activity of the antibiotic and broadening of its antibacterial spectrum. This work was done experimentally and in humans. Assays of both molecules were performed by HPLC. During a 3 h perfusion of five isolated rabbit liver preparations, 1.3 +/- 0.2% and 0.4 +/- 0.1% of TIC and CA added to the circulating blood were eliminated in the bile. At the same time, 31.8% of TIC and 50.5% of CA were submitted to a hepatic biotransformation. In healthy subjects (n = 5), after a single i.v. injection of 3.2 g of Claventin (TIC: 3 g + CA: 0.2 g) mean peak concentrations of 66.8 +/- 31.9 micrograms/ml (TIC 4th h) and 0.3 +/- 0.1 microgram/ml (CA, 2nd h) were observed in the aspirated duodenal fluid where 0.07% and 0.01%, respectively, of the administered dose were recovered during the 4 h investigation period. In cholecystectomized patients (n = 10) provided with a T-tube, i.v. administration of Claventin, 3.2 g, resulted in biliary maximal levels of 177 +/- 49 micrograms/ml (TIC: 2nd h) and 2.7 +/- 0.5 microgram/ml (CA 1st h). Total amount of each derivative eliminated in bile over 12 h averaged 0.28% (TIC) and 0.05% (CA) of the given dose. Hepatobiliary clearance was 20.5 ml/h (TIC) and 4.4 ml/h (CA). In intra-operative simultaneously sampled specimens of serum, choledochal bile, gallbladder bile and gallbladder wall, the following concentrations were measured 1 h after i.v. administration of Claventin: TIC: 105 +/- 10; 386 +/- 66; 72 +/- 20 micrograms/ml and 36 +/- 11 micrograms/g, CA: 3.5 +/- 0.7; 5.9 +/- 1.5; 0.3 +/- 0.3 microgram/ml and 0.1 +/- 0.1 microgram/g. The biliary pharmacokinetics determined in humans makes it possible to consider favourably the prophylactic use of Claventin in surgery of the biliary tree and constitute a good prerequisite for a possible beneficial treatment of biliary tract infections.