HI concentration was quantified in plasma by the use of a luminescent oxygen channelling immunoassay as described previously [21 (link)]. The lower limit of quantification (LLOQ) of the assay was 25 pmol/l. Samples were analysed in duplicate; results were reported as the mean of the two replicates.
For toxicokinetic analysis, composite mean profiles of plasma concentration versus time data from male and female rats were generated and subsequently treated as full profiles. The steady state concentrations (Css) were calculated based on noncompartmental analysis. For a continuous i.v. infusion of HI, the plasma concentration of HI is per definition constant at all time points. For Day 1, the concentrations from 6 to 24 h represent Css, as steady state is theoretically obtained after 5–7 half-lives (half-life of HI in rats is approximately 14 min [28 (link)]). Hence, on Day 1 from 6 to 24 h and for all time points on day 53, mean plasma concentrations for each animal and for each HI-infused group were calculated to yield individual and group mean Css. Toxicokinetic calculations were performed in Phoenix™ WinNonlin® version 6.2, build 6.2.0.495 (Pharsight®, St. Louis, Missouri, USA).
For toxicokinetic analysis, composite mean profiles of plasma concentration versus time data from male and female rats were generated and subsequently treated as full profiles. The steady state concentrations (Css) were calculated based on noncompartmental analysis. For a continuous i.v. infusion of HI, the plasma concentration of HI is per definition constant at all time points. For Day 1, the concentrations from 6 to 24 h represent Css, as steady state is theoretically obtained after 5–7 half-lives (half-life of HI in rats is approximately 14 min [28 (link)]). Hence, on Day 1 from 6 to 24 h and for all time points on day 53, mean plasma concentrations for each animal and for each HI-infused group were calculated to yield individual and group mean Css. Toxicokinetic calculations were performed in Phoenix™ WinNonlin® version 6.2, build 6.2.0.495 (Pharsight®, St. Louis, Missouri, USA).
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