TY - JOUR
T1 - Effect of altered tissue binding on the disposition of barbital in the isolated perfused rat liver
T2 - Application of the axial dispersion model
AU - Chou, Chen Hsi
AU - Rowland, Malcolm
N1 - Funding Information:
One of us (C.-H.C.) thanks the Ministry of Education of Taiwan, R.O.C., for a grant. We are grateful to SmithKline Beecham Pharmaceuticals (UK) for the supply of [14C]barbital.
PY - 1997/11
Y1 - 1997/11
N2 - To examine the dependence of hepatic dispersion on tissue binding, the distribution kinetics of barbital under varying conditions of barbiturate perfusate concentrations was studied in the isolated perfused rat liver preparation (n = 5). The in situ liver was perfused in a single-pass mode with protein-free Krebs bicarbonate medium (15 mL/min). During steady-state infusion with various barbiturate concentrations (barbital, 1 g/L; butethal, 0.1, 1 g/L), a bolus containing [3H]water (cellular space marker) and [14C]barbital was injected into the portal vein. The recoveries of [3H]water and [14C]barbital were complete. The mean transit time and hence the volume of distribution for barbital in the absence of bulk barbiturate concentration (56 s and 1.24 mL/g) were about 2-fold higher than those for water (29 s and 0.58 mL/g), and they decreased progressly as the perfusate barbiturate concentration increased, indicating a decrease in tissue binding. However, the relative dispersion values (CV2(H)) of water (0.60) and barbital (0.66) were about the same magnitude and independent of the bulk concentration of barbiturate. The one-compartment dispersion model adequately described the data of barbital with a constant D(N) (dispersion number) value of 0.35. The results indicate that varying the tissue binding of barbital does not change the magnitude of D(N); as such it offers a new experimental approach to examine the hepatic dispersion of solutes with a large distribution volume.
AB - To examine the dependence of hepatic dispersion on tissue binding, the distribution kinetics of barbital under varying conditions of barbiturate perfusate concentrations was studied in the isolated perfused rat liver preparation (n = 5). The in situ liver was perfused in a single-pass mode with protein-free Krebs bicarbonate medium (15 mL/min). During steady-state infusion with various barbiturate concentrations (barbital, 1 g/L; butethal, 0.1, 1 g/L), a bolus containing [3H]water (cellular space marker) and [14C]barbital was injected into the portal vein. The recoveries of [3H]water and [14C]barbital were complete. The mean transit time and hence the volume of distribution for barbital in the absence of bulk barbiturate concentration (56 s and 1.24 mL/g) were about 2-fold higher than those for water (29 s and 0.58 mL/g), and they decreased progressly as the perfusate barbiturate concentration increased, indicating a decrease in tissue binding. However, the relative dispersion values (CV2(H)) of water (0.60) and barbital (0.66) were about the same magnitude and independent of the bulk concentration of barbiturate. The one-compartment dispersion model adequately described the data of barbital with a constant D(N) (dispersion number) value of 0.35. The results indicate that varying the tissue binding of barbital does not change the magnitude of D(N); as such it offers a new experimental approach to examine the hepatic dispersion of solutes with a large distribution volume.
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U2 - 10.1021/js960481d
DO - 10.1021/js960481d
M3 - Article
C2 - 9383746
AN - SCOPUS:0030657670
SN - 0022-3549
VL - 86
SP - 1310
EP - 1314
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 11
ER -