Models of hepatic elimination: implications from studies of the simultaneous elimination of taurocholate and diazepam by isolated rat liver under varying conditions of binding.
Various kinetic models have been developed to describe the elimination of substances by the liver, but there is no agreement about which model is the most appropriate, as experimental evaluation is incomplete and results conflict. We have shown previously that hepatic elimination of taurocholate is best described by models that embody a high degree of sinusoidal heterogeneity or mixing, whereas another study showed that elimination of diazepam is best described by models that embody a low degree of sinusoidal heterogeneity or mixing. To investigate this discrepancy we examined, in the isolated perfused rat liver, the simultaneous elimination of taurocholate and diazepam. The effect on hepatic availability of varying unbound fraction (fu) in a single pass, steady-state system was studied in six experiments for taurocholate (fu, 0.066-0.966) and diazepam (fu, 0.051-0.675) by varying perfusate albumin concentration (0-60 g l-1). As before, elimination of taurocholate was best described by models that embody a high degree of sinusoidal heterogeneity or mixing (i.e., venous equilibrium model, dispersion model with dispersion number = infinity). Diazepam elimination was best described by models that embody a low degree of sinusoidal heterogeneity or mixing (undistributed sinusoidal model, dispersion model with low dispersion number = 1.04). A third model, a distributed model incorporating heterogeneity of sinusoidal blood flows and intrinsic clearances, fitted the data for both taurocholate and diazepam. The fitted coefficients of variation of both flow and intrinsic clearance among the sinusoids were large for taurocholate (176 and 164, respectively), but for diazepam blood flow was large (200) whereas that for intrinsic clearance was small (0.807).(ABSTRACT TRUNCATED AT 250 WORDS)
University of Melbourne Department of Medicine, Austin Hospital, Victoria, Australia.
M S
MS
Ching
D J
DJ
Morgan
R A
RA
Smallwood
D000818:Animals; D003975:Diazepam / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051381:Rats; D011919:Rats, Inbred Strains; D013656:Taurocholic Acid / Q000378:metabolism*
D013656:Taurocholic Acid; D003975:Diazepam