Influence of sepsis on the plasma elimination pharmacokinetics of diaspirin crosslinked hemoglobin in rats.

Abstract

Septic shock is characterized by abnormalities in microcirculatory O2 delivery (QO2) and profound tissue O2 debt. Administration of crosslinked hemoglobin may be a means of augmenting the QO2 and tissue O2 availability. Sepsis is associated with hemodynamic and metabolic alterations which may affect the pharmacokinetics of crosslinked hemoglobin. The objective of this study was to determine the effect of sepsis on the plasma elimination of diaspirin crosslinked hemoglobin (DCLHb). Twenty-four hours after the induction of sepsis by cecal ligation and perforation, septic (n = 9) and sham rats (n = 8) received an intravenous infusion of 300 mg of DCLHb and arterial blood samples were taken at regular intervals to determine free plasma hemoglobin concentration. DCLHb elimination in septic and sham rats was consistent with first-order elimination kinetics. The half life (t1/2) for septic rats was 4.2 +/- 0.7 h and was significantly shorter than the t1/2 of non-septic rats (5.4 +/- 0.9 h). In all rats, free plasma hemoglobin returned to basal levels by 24 hours after DCLHb administration. The volume of distribution for DCLHb in the septic and non-septic rats was not significantly different and suggests that DCLHb is not influenced by altered gut permeability. Despite significant changes in some elimination parameters the differences were small. Consequently, dosing regimens for this compound may not need to be altered in sepsis.