Metabolism of the prodrug lisdexamfetamine dimesylate in human red blood cells from normal and sickle cell disease donors *

摘要

Objectives Lisdexamfetamine dimesylate (LDX), a long-acting pro-drug psychostimulant, requires conversion to d-amphetamine for therapeutic activity. Conversion of LDX to d-amphetamine occurs primarily in the blood, specifically red blood cells (RBCs). These in vitro studies examine potential conversion in blood-containing pathologically deformed RBCs. Methods Fresh blood samples from two human male donors with sickle cell disease and two healthy control donors were incubated for up to 4?h with LDX (1?μg/mL) at 37°C. LDX and d-amphetamine were measured by a validated liquid chromatographic mass spectrometric (LC/MS/MS) method. Results In incubations of blood from the two donors with sickle cell disease, LDX concentrations declined over time such that 14.1% and 15.3% of initial LDX remained after 4?h. Similarly, in incubations of blood from two healthy donors, LDX concentrations declined over time with 13.1% and 10.5% of initial LDX remaining. Half-life of LDX was 1.30 and 1.36?h for the donors with sickle cell disease and 1.15 and 1.13?h for the healthy donors. Concurrent with the decrease in LDX concentrations, the d-amphetamine concentrations rose in a similar fashion in samples from healthy controls and sickle cell donors. d-Amphetamine levels detected at 4?h with LC/MS/MS were 297.0?ng/mL and 324.3?ng/mL in the two healthy donors and 304.5?ng/mL and 286.6?ng/mL in the two sickle cell donors. Conclusions While the current findings are derived from in vitro investigations on a small number of samples and the applicability of this in vitro experimental system to in vivo function has not been established, biotransformation of LDX and the resulting delivery of active d-amphetamine from LDX are likely to be similar in individuals with or without sickle cell disease.