In Vivo Red Blood Cells/Plasma Partition Coefficient of Treosulfan and Its Active Monoepoxide in Rats

Abstract

Background and objectives: Treosulfan is a prodrug applied in the treatment of ovarian cancer and conditioning prior to stem cell transplantation. So far, the bioanalysis of treosulfan in either whole blood or red blood cells (RBC) has not been carried out. In this work, the RBC/plasma partition coefficient (K_e/p) of treosulfan and its active monoepoxide was determined for the first time.

Methods: Male and female 10-week-old Wistar rats (n = 6/6) received an intraperitoneal injection of treosulfan at the dose of 500 mg/kg body weight. The concentrations of treosulfan and its monoepoxide in plasma (C_p) and RBC were analyzed with a validated HPLC-MS/MS method.

Results: The mean K_e/p of treosulfan and its monoepoxide were 0.74 and 0.60, respectively, corresponding to the blood/plasma partition coefficient of 0.88 and 0.82. The Spearman test demonstrated that the K_e/p of the prodrug correlated with its C_p, but no correlation between the K_e/p and C_p of the active monoepoxide was observed.

Conclusions: Treosulfan and its monoepoxide achieve higher concentrations in plasma than in RBC; therefore, the choice of plasma for bioanalysis is rational as compared to whole blood. The distribution of treosulfan into RBC may be a saturable process at therapeutic concentrations.

Fig. 1

Plot of the K_e/p of treosulfan and S,S-EBDM against C_p following intraperitoneal bolus injection of treosulfan at the dose of 500 mg/kg body weight. The solid and dotted lines show the mean ± standard deviation. C_p drug concentration in plasma, K_e/p red blood cells/plasma partition coefficient