Abstract
The regulatory mechanism responsible for a paradoxal, rapid drop in the erythropoietin (EPO) plasma level seen 2 to 4 days after acute, phlebotomy-induced anemia was investigated in seven adult sheep. To introduce acute anemia, each sheep underwent two phlebotomies where the hemoglobin (Hb) was reduced to 3 or 4 g/dl over 4 to 5 h. The phlebotomies were spaced 4 to 6 weeks apart in three animals, and 8 days apart in four other animals. EPO plasma levels, reticulocyte count, Hb, and p50 for oxygen-Hb dissociation were determined from frequent blood samplings throughout the study period. EPO's disposition pharmacokinetic (PK) and plasma clearance were determined from i.v. bolus injections of tracer amounts of a recombinant human EPO tracer. The controlled drop in Hb resulted in a rapid increase in plasma EPO to 836 ± 52 mU/ml (mean ± coefficient of variation percentage) that was followed by a paradoxical rapid drop 2 to 4 days after the phlebotomy while the animals were still very anemic (Hb = 4.3 ± 15 g/dl). The rapid drop in plasma EPO level could not be explained by the up-regulated clearance (clearance increased by a factor of less than 2.5) or by physiological adaptation (no change in p50, p > 0.05, second phlebotomy to Hb = 3g/dl inadequately stimulated the EPO production). The PK/pharmacodynamic (PD) analysis supports the hypothesis of a limited sustained high EPO production rate in acute anemia, which indicates an apparent deficiency in the regulation of EPO production in acute anemia. The hypothesis was supported by a PK/PD feedback inhibition model that showed good agreement with the data (r = 0.973 ± 1.57).
Footnotes
-
This work is supported by the United States Public Health Service National Institutes of Health Grants P01 HL46925 and R21 GM57367 and Grant RR000359 from the General Clinical Research Center Program, National Center for Research Resources, National Institutes of Health, and by the Veterans Administration Medical Center, Iowa City, IA.
-
DOI: 10.1124/jpet.104.066027.
-
ABBREVIATIONS: EPO, erythropoietin; Hb, hemoglobin; PK, pharmacokinetics; PD, pharmacodynamics; UIR, unit impulse response; rhEPO, recombinant human erythropoietin; RIA, radioimmunoassay; EPOR, EPO receptor.
- Received January 22, 2004.
- Accepted February 26, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|