TY - JOUR T1 - Blood Thiols Following Amifostine and Mesna Infusions, a Pediatric Oncology Group Study JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1460 LP - 1466 VL - 29 IS - 11 AU - Abdul-Kader Souid AU - Robert C. Fahey AU - Mehmet K. Aktas AU - Omer A. Sayin AU - Sara Karjoo AU - Gerald L. Newton AU - Peter D. Sadowitz AU - Ronald L. Dubowy AU - Mark L. Bernstein Y1 - 2001/11/01 UR - http://dmd.aspetjournals.org/content/29/11/1460.abstract N2 - The Pediatric Oncology Group study for metastatic Ewing's sarcoma used amifostine and mesna with the alkylating agents. To determine the fate of combined drug thiols, we measured thiol levels in plasma, red blood cells (RBC), and peripheral blood mononuclear cells (PBMC) of four patients. We also conducted analogous measurements on two patients who received mesna alone and a volunteer's blood following in vitro treatment. Thiols were labeled with monobromobimane, separated on high-pressure liquid chromatography, and detected by fluorescence. Incubation of a volunteer's blood with mesna, WR-1065, or both revealed that cellular uptake of total reducible drug was ∼10% of plasma level for mesna but ∼60% for WR-1065. Cellular drugs were mainly the thiol form, whereas half of the plasma drugs were disulfides. Combined incubation with both thiols did not change the extent or form of uptake. WR-1065 and mesna prevented glutathione depletion by 4-hydroperoxycyclophosphamide. Results from patients were similar. WR-1065 and mesna appeared in the cells by the end of the drug infusions, although WR-1065 uptake was more efficient than mesna. The concentration-time profiles of mesna in RBC paralleled those in plasma. Amifostine administration during mesna infusion caused transient increase in mesna levels. Both agents increased blood cysteine and decreased total reducible cysteine. Mesna alone and mesna plus amifostine prevented cellular glutathione depletion. In conclusion, mesna is imported by RBC and PBMC, but less efficiently than WR-1065. When present at equal levels, these thiols do not influence each other's uptake. Adequate dosing of either drug is necessary for protecting the cells from toxic effects of alkylating agents. The American Society for Pharmacology and Experimental Therapeutics ER -