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Metabolism of thrombopoietin (TPO) in vivo: determination of the binding
dynamics for TPO in mice
E Stefanich, T Senn, R Widmer, C Fratino, GA Keller and PJ Fielder
Department of Pharmacokinetics and Metabolism, Genentech Inc, S San
Francisco, CA 94080, USA.
Previous in vivo studies have established that plasma thrombopoietin (TPO)
levels are regulated by binding to c-Mpl on platelets and that, in vitro,
platelets bind and degrade TPO. To determine if the in vivo metabolism of
TPO was specific and saturable, we injected normal CD-1 mice IV with trace
amounts of 125I-rmTPO with or without a saturating concentration of rmTPO.
The amount of radioactivity present in the spleen, blood cell fraction,
platelet fraction, tibia/fibula, and femur was significantly greater in the
mice receiving 125I-rmTPO alone. Conversely, the amount of radioactivity
present in the plasma was significantly greater in the mice receiving both
125I-rmTPO and rmTPO, thus suggesting the uptake of rmTPO by the spleen,
platelets, and bone marrow in vivo was saturable. Platelet and spleen
homogenates from animals receiving 125I-rmTPO alone showed a degradation
pattern of 125I- rmTPO similar to that observed in vitro using mouse
platelet rich plasma. To determine the in vivo binding dynamics for rmTPO,
mice were injected with 125I-rmTPO alone or with increasing concentrations
of rmTPO; spleen and blood cell-associated radioactivity was determined at
2 hours postinjection. A 4-parameter curve fit of the data indicated that
the "in vivo binding affinity" for rmTPO was approximately 6.4 microg/kg.
These data indicate that after a dose of approximately 6.4 microg/kg, 50%
of all c-Mpl receptors will be saturated with rmTPO. Electron microscopy
indicated that radioactivity was present bound to and within megakaryocytes
and platelets in both sternum and spleen and platelets in circulation.
Together these data demonstrate that in vivo, 125I-rmTPO is mainly
metabolized by platelets and to a small extent by cells of the
megakaryocyte lineage, via a specific and saturable mechanism.
Volume 89,
Issue 11,
pp. 4063-4070,
06/01/1997
Copyright © 1997 by The American Society of Hematology
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