Biology Reference
In-Depth Information
approximately six-fold higher at 10 U/kg than at 1,000 U/kg. It should be
noted that none of these clinical studies addressed the potential for degradation
products to exist in the urine.
Role of liver
The liver has been suggested as another possible clearance organ, perhaps of a
metabolite. One theory is that the sialic acids are removed by sialidases in the
blood and/or tissue, thus exposing the penultimate galactose residues that
makes the desialylated form a substrate for the asialo-glycoprotein receptor in
the liver [55].
Ex vivo
desialylation of rHuEPO resulted in much more rapid
clearance in rats after intravenous administration than the intact form [55, 60].
Little evidence suggests that intact rHuEPO is cleared directly from the liver
[54]. In a rat disease-state model (induced by d-galactosamine-HCl), although
Dinkelaar et al. [59] found a small but significant elongation in the plasma dis-
appearance time compared with control animals (164 min compared with
105 min), they dismissed the role of the liver in EPO catabolism as minor at
best, as their own
in vitro
perfusion studies did not support the findings.
Additionally, evidence for the
in vivo
action of sialadases is lacking. Although
sialic acid removal may not be the
in vivo
mechanism of clearance, it is clear
that the presence of sialic acids on these molecules enables them to remain in
circulation [60].
Role of bone marrow
The bone marrow has been suggested, not only as the effector organ but also
as a clearance organ. It has been demonstrated that rHuEPO is internalized and
degraded by its target cells [61]. These authors demonstrated with mice spleen
cells, which have cell-surface EPO receptors (EPOR), that between 40% and
60% of total radiolabeled EPO specifically bound to the cell was internalized
and that degradation occurred, most likely through the lysosomes; the fate of
EPOR was not determined, i.e., recycled or degraded. Kato el al. [54] demon-
strated saturable uptake of rHuEPO by the bone marrow (and spleen), which
they postulated was mediated by EPOR. Bowen et al. [50] found reduced
clearance of rHuEPO for patients with myelodysplastic syndromes. A poten-
tial implication of EPOR-mediated clearance is that any organ with EPOR
(e.g., liver, brain, spleen) has the potential to be a clearing organ to some
extent. The involvement of progenitor cells, or more broadly EPOR-bearing
cells, may help explain observations of increased clearance upon multiple dos-
ing wherein the pool of cells has expanded.
