Ocular disposition of treosulfan and its active epoxy-transformers following intravenous administration in rabbits.
Treosulfan (TREO) has an established position in chemotherapy of advanced ovarian cancer but has been also applied in uveal melanoma patients. Moreover, it is used as an orphan drug for a myeloablative conditioning prior to stem cell transplantation. In this paper, biodistribution of prodrug TREO and its active monoepoxide (S,S-EBDM) and diepoxide (S,S-DEB) into aqueous humor of the eye was studied for the first time. For that purpose, alone TREO and the mixture of TREO, S,S-EBDM and S,S-DEB were administered intravenously to New Zealand White rabbits. The three analytes were determined in plasma and aqueous humor by validated HPLC methods and pharmacokinetic calculations were performed in WinNonlin. After the infusion of TREO, the aqueous humor/plasma Cmaxratio and area under the curve ratio amounted 0.04 and 0.10 for TREO, and 1.1 and 2.2 for S,S-EBDM, respectively. Following the bolus injection of the mixture of the prodrug and its epoxides, the aqueous humor/plasma Cmaxratios for TREO, S,S-EBDM and S,S-DEB were 0.05, 0.66, and 4.0, respectively. The presented results indicate a poor penetration of TREO into the eye, which may impair systemic treatment of ocular tumors but is beneficial in terms of a lack of clinically relevant ophthalmic adverse effects.
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland. Electronic address: michalroman@ump.edu.pl.
Michał
M
Romański
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland. Electronic address: akasprzy@ump.edu.pl.
Anna
A
Kasprzyk
Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, 14 St. Mary Magdalena Street, 61-861 Poznań, Poland. Electronic address: agakaminska82@o2.pl.
Agnieszka
A
Karbownik
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland. Electronic address: glowka@ump.edu.pl.
Franciszek K
FK
Główka
D061605:Administration, Intravenous / Q000379:methods; D000818:Animals; D002066:Busulfan / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004852:Epoxy Compounds / Q000378:metabolism / Q000494:pharmacology; D005123:Eye / Q000378:metabolism*; D005260:Female; D008297:Male; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D014018:Tissue Distribution
D004852:Epoxy Compounds; D011355:Prodrugs; C018404:treosulfan; D002066:Busulfan
Blood – aqueous barrier; Epoxides; HPLC; Permeability; Pharmacokinetics; Prodrug; Uveal melanoma