Urinary elimination of cyclophosphamide alkylating metabolites and free thiols following two administration schedules of high-dose cyclophosphamide and mesna

Abstract

Twenty patients with a variety of neoplastic diseases were treated with preparative regimens containing high-dose cyclophosphamide (CY) administered as a 2-h infusion (60 mg/kg) for 2 days or by continuous infusion (1500 mg/m2/day) for 4 days. In patients receiving CY by 2-h infusion, the uroprotectant 2-mercaptoethane sulfonate (MESNA) was administered as an intermittent, bolus intravenous infusion (20% of CY dose) every 6 h. In patients receiving continuous infusion CY, MESNA was administrated concomitantly at an equivalent dose to CY by continuous infusion. During the first 24 h of CY administration, urine was collected at 2-h intervals and analyzed for free thiols and CY-alkylating metabolites. In patients receiving CY by short infusion and MESNA by intermittent bolus infusion, urinary concentrations of alkylating metabolites peaked at 4-8 h. During each dose of MESNA, urinary free thiols peaked at 2 h following administration but fell to pre-treatment levels at subsequent intervals. In patients receiving CY by continuous infusion, CY alkylating metabolites increased gradually over the 24-h study period while free thiols remained at a constant level during this period. With bolus administration of CY and intermittent bolus administration of MESNA every 6 h, there are periods where urinary CY-alkylating metabolites are elevated and free thiol concentrations are diminished. During continuous infusion of CY and MESNA, urinary CY alkylating metabolites reached peak concentrations at 18-22 h while the exposure of the bladder to free thiols remained constant. Recommendations are provided to increase the exposure of free thiols in the bladder when MESNA is administered by bolus or continuous infusion.