Metabolism of the prodrug lisdexamfetamine dimesylate in human red blood cells from normal and sickle cell disease donors
Year: 2013
Type: article
Abstract: 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.
Source: Journal of Drug Assessment
Author: Michael Pennick
Institution: Shire (United Kingdom)
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2206890544