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Comparative Study
. 2018 Oct;43(5):565-571.
doi: 10.1007/s13318-018-0469-7.

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

Michał Romański  1 , Anna Zacharzewska  1 , Artur Teżyk  2 , Franciszek K Główka  3
Affiliations
Comparative Study

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

Michał Romański et al. Eur J Drug Metab Pharmacokinet. 2018 Oct.

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 (Ke/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 (Cp) and RBC were analyzed with a validated HPLC-MS/MS method.

Results: The mean Ke/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 Ke/p of the prodrug correlated with its Cp, but no correlation between the Ke/p and Cp 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.

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Conflict of interest statement

Conflict of interest

The authors, M. Romański, A. Zacharzewska, A. Teżyk, and F.K. Główka, have no conflict of interest to declare.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The studies were approved by the Local Ethics Committee for Experimental on Animals in Poznan, Poland (Approval no. 11/2016).

Figures

Fig. 1
Fig. 1
Plot of the Ke/p of treosulfan and S,S-EBDM against Cp 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. Cp drug concentration in plasma, Ke/p red blood cells/plasma partition coefficient
See this image and copyright information in PMC

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