Disposition of treosulfan and its active monoepoxide in a bone marrow, liver, lungs, brain, and muscle: Studies in a rat model with clinical relevance

Treosulfan Pharmacokinetics and its Variability in Pediatric and Adult Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation: Current State of the Art, In-Depth Analysis, and Perspectives

“…Consequently, the t ½ of S,S-EBDM and S,S-DEB is the same as that of treosulfan, despite the levels of epoxides in the body being very low compared with the prodrug due to their high Cl tot [ 17 ]. Additional confirmation for this phenomenon was provided by an observation that the organ elimination of S,S-EBDM in rats proceeded at a similar rate as that of treosulfan (lungs, muscle, and bone marrow), except the brain, from which the epoxide was eliminated faster [ 19 ]. A clinical importance of the above facts is that once the elimination of treosulfan is completed, S,S-EBDM and S,S-DEB are also eliminated from the patient’s body.…”

“…To date, the binding of treosulfan to human plasma and tissue proteins has not been examined under physiological pH to avoid the epoxy transformation of the parent drug. However, it is worth noting that the drug recovery from acidified human plasma after 10 kDa ultrafiltration cut-off was 96 ± 4% [ 31 ], and its unbound fraction in acidified rat plasma and tissue homogenates exceeded 0.94 [ 18 , 19 ]. Moreover, the in vivo ratio of the area under the curve (AUC) of treosulfan in rat liver, lungs, muscle, and bone marrow to its AUC in plasma ranged from 0.8 to 1.0 [ 19 ].…”

“…However, it is worth noting that the drug recovery from acidified human plasma after 10 kDa ultrafiltration cut-off was 96 ± 4% [ 31 ], and its unbound fraction in acidified rat plasma and tissue homogenates exceeded 0.94 [ 18 , 19 ]. Moreover, the in vivo ratio of the area under the curve (AUC) of treosulfan in rat liver, lungs, muscle, and bone marrow to its AUC in plasma ranged from 0.8 to 1.0 [ 19 ]. The above properties, along with a nonelectrolyte character of treosulfan, provide indirect evidence for a very weak binding of the drug to plasma and tissue proteins.…”

“…The above properties, along with a nonelectrolyte character of treosulfan, provide indirect evidence for a very weak binding of the drug to plasma and tissue proteins. Moreover, the practically complete bioavailability of treosulfan in humans after oral administration, and its almost homogenous distribution in rat plasma, liver, lungs, and bone marrow, demonstrate that the drug easily crosses biological membranes, despite being hydrophilic (log of octanol/water partition coefficient − 1.58) [ 19 , 32 , 33 ]. Based on the average values of the V ss of treosulfan (Tables 1 and 2 ), it may be concluded that the drug distributes into extracellular fluid and a part of intracellular fluid.…”

“…In a rat model, the prodrug was eliminated from the brain two times slower than from blood and other organs, but the corresponding t ½ was still relatively short. Therefore, a washout period of at least 2 days, which is used after treosulfan administration in conditioning prior to HSCT, can be considered sufficient to prevent the graft from drug exposure [ 19 ].…”