Abstract
Albumin, the most abundant plasma protein, not only controls osmotic blood pressure, but also serves as a carrier for various small molecules, including pharmaceuticals. Its impact on pharmacological properties of many drugs has been extensively studied over decades. Here, we focus on its interaction with the following mobilizing agents: Granulocyte-colony stimulating factor (G-CSF) and AMD3100, where such analyses are lacking. These compounds are widely used for hematopoietic stem cell mobilization of healthy donors or patients. Using albumin-deficient (Alb−/−) mice, we studied the contribution of albumin to mobilization outcomes. Mobilization with the bicyclam CXCR4 antagonist AMD3100 was attenuated in Alb−/− mice compared to wild-type littermates. By contrast, mobilization with recombinant human G-CSF (rhG-CSF), administered twice daily over a five-day course, was significantly increased in Alb−/− mice. In terms of a mechanism, we show that rhG-CSF bioavailability in the bone marrow is significantly improved in Alb−/− mice, compared to wild-type (WT) littermates, where rhG-CSF levels dramatically drop within a few hours of the injection. These observations likely explain the favorable mobilization outcomes with split-dose versus single-dose administration of rhG-CSF to healthy donors.
Highlights
Albumin is, by a wide margin, the most abundant plasma protein of all higher species, including man, typically at concentrations of 30–50 g/L
In order to assess the effect of albumin deficiency on hematopoietic stem cell mobilization, we first enumerated phenotypically and functionally mature and immature hematopoietic cells in all hematopoietic organs of untreated young adult Alb−/− mice, or wild-type littermates as baseline values
The number of functional hematopoietic stem and progenitor cells (HSPC) (CFU-C) in all hematopoietic compartments was unaffected by albumin deficiency (Figure 1B and Figure S1B), whereas the number of phenotypic HSPC
Summary
By a wide margin, the most abundant plasma protein of all higher species, including man, typically at concentrations of 30–50 g/L. It controls colloid osmotic pressure [1,2,3] and serves as a depot and a carrier for both endogenous small molecules and medicinal substances [4]. The model was intended to facilitate substitution of mice with human serum albumin, which increases albumin half-life, from 2.6 to 4.2 days, allowing for the study of drug binding to human albumin in mice. Albumin deficient (Alb−/−) mice are viable and healthy; they compensate for the lack of serum albumin by increasing plasma levels of triglycerides, cholesterol, and aspartate aminotransferase. The total serum protein level is still significantly lower than in wild-type mice and comparable to hypoalbuminemic patients [9,10]
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