Hepatic disposition of trimethoprim and sulfamethoxazole

Hepatic disposition of trimethoprim (TMP) and sulfamethoxazole (SMX) and the liver distributional volumes were investigated in the in situ perfused rat liver preparation. Perfusion experiments were conducted using Krebs-bicarbonate buffer delivered via the portal vein (15 ml/min) in a single-pass mode. Erythrocytes (intravascular marker) and Evans blue (extracellular marker) were used for the estimation of liver distributional volumes, and desiccation and freeze-drying methods were used for the estimation of liver water content. TMP and SMX were administered together as a bolus in the presence (1%) and absence of protein. Although SMX profiles displayed a characteristic sharp peak followed by a slower eluting tail in all cases, TMP profiles were dependent on protein; in the absence of protein, the early sharp peak was replaced by a flatter profile with a later peak. Fractional effluent recovery (F; 0.77 vs. 0.82) and hepatic clearance (CL_H; 3.44 vs. 2.70 ml/min) for TMP were not influenced by albumin; with SMX, F increased (0.32 vs. 0.60) and CL_H decreased (10.2 vs. 6.0 ml/min) with an increase in the perfusate protein concentration. Hepatic extraction of TMP was low (<0.30), whereas it was intermediate (<0.70)for SMX. In addition, distributional volumes and total water content of the liver were successfully determined.