Reduction in biliary excretion of ceftriaxone by diclofenac in rabbits

The effects of diclofenac, a nonsteroidal anti-inflammatory drug, on biliary excretion of ceftriaxone were evaluated in rabbits. In a previous study, we demonstrated that diclofenac increased the extravascular diffusion and antibacterial efficacy of ceftriaxone without any effect on serum protein binding and urinary excretion of this antibiotic. We perfected a surgical procedure that allowed the study of biliary secretion in conscious rabbits with a stable hemodynamic state. The kinetic study was carried out on the fourth day of treatment with ceftriaxone alone (30 mg/kg per day given intramuscularly; group 1) or combined with diclofenac (1.5 mg/kg per 12 h given intramuscularly; group 2). Cumulative biliary excretion of ceftriaxone over 6 h was significantly reduced in group 2 (5,291.6 +/- 2,017.5 micrograms in group 1 versus 1,379.1 +/- 567.1 micrograms in group 2). This phenomenon occurred without any change in biliary flow. Indocyanine green clearance (20 mg/kg) increased in animals treated with ceftriaxone alone compared with the saline-treated control group (55.04 +/- 4.68 versus 33.29 +/- 7.52 ml/min per kg, respectively). Diclofenac alone caused a significant decrease in indocyanine green clearance compared with clearance in controls (25.05 +/- 4.74 versus 33.29 +/- 7.52 ml/min per kg), and indocyanine green clearance appeared not significantly different from control values in animals receiving ceftriaxone plus diclofenac. These results suggest that (i) ceftriaxone could increase hepatic blood flow and (ii) reduction of the hepatic clearance of ceftriaxone by diclofenac may be due to hepatic hemodynamic variations involving diclofenac inhibition of prostaglandin synthesis, although an interaction of diclofenac with hepatic uptake of ceftriaxone cannot be ruled out.