Receptor-mediated clearance of a recombinant human granulocyte
colony-stimulating factor derivative nartograstim in bone marrow of
rats.
Kuwabara, Takashi, Tatsuo Uchimura, Hiroyuki Kobayashi, Satoshi
Kobayashi, and Yuichi Sugiyama.
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd.,
Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411, Japan (T.K.,
T.U., H.K. and S.K. ), Faculty of Pharmaceutical Sciences, University
of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan (Y.S.)
APStracts 2:0016E, 1995.
To clarify the role of the granulocyte colony-stimulating factor (G
-CSF) receptor in the non-linear elimination of a recombinant human G
-CSF derivative, nartograstim (NTG), the accompanying changes in the
in vivo NTG total body clearance at steady-state (CLss) or the early
phase tissue uptake clearance (CLuptake) in rats were compared with
the change in the number of G-CSF receptors in bone marrow. The
infusion rate-dependent decrease in CLss in control rats confirmed
the existence of a saturable elimination mechanism for NTG. The Km
and Vmax values for this saturable process were estimated to be 107
pM and 15.5 pmol/hr/kg. The K[mu] value for this saturable process was
comparable with the Kd value for the specific binding of NTG to bone
marrow cells. After administration of excess NTG, the CLuptake of
tracer amounts of 125I-NTG by bone marrow and spleen, which
corresponds to the receptor density in the tissues, were reduced at 2
hr but gradually recovered. This change in CLuptake corresponds well
to the change in the in vitro NTG binding capacity in each isolated
cell. This reduction in CLuptake might be due to the down-regulation
of G-CSF receptors on the cell surface. On the other hand, the
saturable CLss in cyclophosphamide-treated rats was 17 % that in
control rats, while the saturable CLss in rats given NTG repeatedly
was 2-fold greater than in controls, which is associated with the up
-regulation of G-CSF receptors. These changes in saturable CLss indeed
corresponded well with those of the in vitro NTG binding capacity in
bone marrow. These findings indicate that the saturable uptake and
elimination of NTG in rats are due to G-CSF receptor-mediated
endocytosis.
Received 17 October 1994; accepted in final form 26 January 1995.
APS Manuscript Number E427-4.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 25 February 1995.