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The pig is probably one of the best mammalian models for studying the digestive functions and the biliary excretion of drugs because of the tight similarities with humans. Insertion of a T drain in the common bile duct after cholecystectomy in humans became uncommon because of surgical progress. For this reason, we developed a model using a bidirectional cannula to study the biliary secretion in the conscious Micropig Yucatan. We used this breed because of their ready availability and low stable weight. The surgical procedure was a double choledococholedocal fistula with a bypass on the main biliary duct, maintaining the continuous flow of bile into the duodenum through the sphincter of Oddi. This fistula remained effective for at least sixty days with normal hepatic biologic parameters. The development of our model could improve the biliary excretion study of drugs. Comparison of different routes of administration and interaction pharmacokinetic studies could also be studied in the same micropig, eliminating intersubject variations.

The biliary elimination and pharmacokinetics of vinorelbine (NVB) were investigated in five conscious micropigs provided with a double-terminal choledocal fistula allowing the collection and reinstillation of bile. After the i.v. administration of NVB (0.5 mg/kg), serum and bile samples were collected over a 48-h period. The concentrations of NVB were measured by high-performance liquid chromatography. The serum concentrations decreased rapidly from a maximal value of 208.6 ng/ml (SD, 111.7 ng/ml). The mean half-life was 10.9 h (SD, 8.6 h) and the mean AUC0-48 h was 292.8 ng ml-1 h (SD, 79.4 ng ml-1 h). The bile concentrations were high, amounting to 16.0 micrograms/ml (range, 5.4-27.7 micrograms/ml). The 0- to 48-h biliary excretion of unchanged NVB accounted for 25.8% (SD, 5.7%) of the injected dose, with 21.5% (SD, 4.0%) being eliminated during the 0- to 8-h period. Desacetyl-NVB was found in an inconstant manner and in very low amounts in bile samples. In addition, no glucuronide of NVB could be detected. Thus, in the micropig, biliary excretion represents an important route of elimination for NVB.

The purpose of the present work was to investigate the 48 h pharmacokinetic and biliary elimination of temafloxacin, administered intraduodenally at a single dose of 10 mg/kg to six conscious pigs provided with a double terminal choledocal fistula allowing the collection and the reinstillation of bile. The concentrations of temafloxacin in biological fluids were measured by both HPLC and bioassay. The mean serum half-life of temafloxacin was 11.45 +/- 4.4 h and the apparent oral clearance (assuming a 95% bioavailability) was 171 +/- 66 mL/min. The penetration of temafloxacin into bile is significant as indicated by a bile/serum AUC ratio of 9.1 +/- 2.2. The 0-45 h biliary excretion amounted to 2.002 +/- 0.8 mg, representing 0.9 +/- 0.3% of the administered dose. Biliary peak concentrations ranged from 8.0 to 37.5 mg/L and the 24 h mean biliary concentration was 3.7 +/- 2.4 mg/L. No statistically significant differences between HPLC and bioassay concentrations or AUCs could be observed in bile, indicating that temafloxacin is not extensively biotransformed into active metabolites in this model. These data, together with data in man, suggest that temafloxacin could be a useful agent for the treatment of biliary tract infections.

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.