Application of the axial dispersion model of hepatic drug elimination to the kinetics of diazepam in the isolated perfused rat liver

Abstract

The application of the axial dispersion model to diazepam hepatic elimination was evaluated using data obtained for several conditions using the single-pass isolated perfused rat liver preparation. The influence of alterations in the fraction unbound in perfusate (fu) and perfusate flow (Q) on the availability (F) of diazepam was studied under steady conditions (n = 4 in each case). Changes in fu were produced by altering the concentration of human serum albumin (HSA) in the perfusion medium while maintaining diazepam concentration at 1 mg L-1. In the absence of protein (fu = 1), diazepam availability was 0.011 +/- 0.005 (mean +/- SD). As fu decreased, availability progressively increased and at a HSA concentration of 2% (g/100 ml), when fu was 0.023, diazepam availability was 0.851 +/- 0.011. Application of the axial dispersion model to the relationship between fu and F provided estimates for the dispersion number (DN) of 0.337 +/- 0.197, and intrinsic clearance (CL(int)) of 132 +/- 34 ml min-1. The availability of diazepam during perfusion with protein-free media was also studied at three different flow rates (15, 22.5, and 30 ml min-1). Diazepam availability always progressively increased as perfusate flow increased, with the axial dispersion model yielding estimates for DN of 0.393 +/- 0.128 and CL(int) of 144 +/- 38 ml min-1. The transient form of the two-compartment dispersion model was also applied to the output concentration versus time profile of diazepam after bolus input of a radiolabeled tracer into the hepatic portal vein (n = 4), providing DN and CL(int) estimates of 0.251 +/- 0.093 and 135 +/- 59 ml min-1, respectively. Hence, all methods provided similar estimates for DN and CL(int). Furthermore, the magnitude of DN is similar to that determined for noneliminated substances such as erythrocytes, albumin, sucrose, and water. These findings suggest that the dispersion of diazepam in the perfused rat liver is determined primarily by the architecture of the hepatic microvasculature.