M. Bazinredureau et al., IMMUNOGLOBULIN-G, F(AB')(2), AND FAB FRAGMENT UPTAKE KINETICS IN ISOLATED-PERFUSED RAT-LIVER AND RAT HEPATIC CELLS, Drug metabolism and disposition, 23(12), 1995, pp. 1400-1406
The interaction of I-125-radiolabeled immunoglobulin G (IgG), F(ab')(2
), and Fab fragments with different modes of production (polyclonal or
monoclonal), belonging to different subclasses (IgG(1) and IgG(T)) an
d derived from different sources (mouse, rat, and horse) with liver, w
as investigated by using isolated perfused rat liver and isolated rat
hepatic parenchymal cells (PCs) and nonparenchymal cells (NPCs) in sus
pension, Lactosaminated-bovine serum albumin (Lac-BSA) and formaldehyd
e-bovine serum albumin were used as markers of specific binding to PCs
and NPCs, respectively, Using the isolated perfused rat liver model,
date clearly indicated a very weak hepatic extraction ratio (<0.003) f
or IgGs and fragments in comparison with Lac-BSA (extraction ratio = 0
.398) over the 3 hr of the experiments. No breakdown or higher molecul
ar weight compounds were observed by sodium dodecyl sulfate-polyacryla
mide gel electrophoresis analysis, Biliary excretion of IgGs and fragm
ents ranged from 0.07 to 0.3%, mainly as free iodine-125, In contrast,
7% of Lac-BSA was excreted unchanged in bile, and 10% of free iodine
was excreted at 3 hr, In vitro binding studies showed no specific bind
ing of any antibody and fragment proteins at 4 degrees C or 37 degrees
C, In contrast, saturable uptake was observed for Lac-BSA with PCs an
d formaldehyde-bovine serum albumin with NPCs, Both models demonstrate
d that nonspecific antibody/fragment interactions occurred with rat li
ver, Several hypotheses can be formulated to explain why liver-antibod
y interactions depend on more complex antibody molecular states (aggre
gated structure and immune complex) rather than the monomeric structur
e investigated in the present study.