Pharmacokinetics, tissue distribution and metabolism of hydroxyethyl starch 130/0.4 in rats

Hydroxyethyl starch (HES) is a clinically utilized polymeric polysaccharide commonly administered intravenously to achieve the pharmacologic effects of maintaining circulating blood volume and improving microcirculation. Its plasma pharmacokinetics, metabolism, and biodistribution are essential for assessing effectiveness and adverse effects. However, the identification of metabolites and direct quantification of HES in vivo present significant challenges due to its complex molecular structure and polydispersity. In this study, we introduce a novel approach to analyzing the pharmacokinetics of HES in rats using liquid chromatography-mass spectrometry, with hydroxyethyl starch 130/0.4 (HES130/0.4) as a model. The findings indicate that HES130/0.4 undergoes rapid metabolism following intravenous administration, predominantly through glycosidic bond cleavage. The molecular weights of the identified metabolites in plasma and urine ranged from 500 to 3400 Da. Metabolites below the renal threshold are preferentially excreted via the kidneys, whereas the macromolecule HES130/0.4 exhibits a large apparent volume of distribution and is cleared from the plasma within 24 h. High concentrations of HES130/0.4 were observed in highly perfused tissues, nonetheless, the metabolism and elimination of HES130/0.4 within tissues occur at a slower rate, posing a risk of tissue accumulation. This study represents the first accurate characterization of the in vivo fate of HES130/0.4, providing a critical foundation for evaluating its efficacy and safety. Furthermore, it establishes a methodological framework for the bioanalysis and comprehensive elucidation of the in vivo fate of other HES variants.