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, 10, 2275-80
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Lisdexamfetamine Prodrug Activation by Peptidase-Mediated Hydrolysis in the Cytosol of Red Blood Cells

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Lisdexamfetamine Prodrug Activation by Peptidase-Mediated Hydrolysis in the Cytosol of Red Blood Cells

Johannah Sharman et al. Neuropsychiatr Dis Treat.

Abstract

Lisdexamfetamine dimesylate (LDX) is approved as a once-daily treatment for attention-deficit/hyperactivity disorder in children, adolescents, and adults in some countries. LDX is a prodrug comprising d-amphetamine covalently linked to l-lysine via a peptide bond. Following oral administration, LDX is rapidly taken up from the small intestine by active carrier-mediated transport, probably via peptide transporter 1. Enzymatic hydrolysis of the peptide bond to release d-amphetamine has previously been shown to occur in human red blood cells but not in several other tissues. Here, we report that LDX hydrolytic activity resides in human red blood cell lysate and cytosolic extract but not in the membrane fraction. Among several inhibitors tested, a protease inhibitor cocktail, bestatin, and ethylenediaminetetra-acetic acid each potently inhibited d-amphetamine production from LDX in cytosolic extract. These results suggest that an aminopeptidase is responsible for hydrolytic cleavage of the LDX peptide bond, although purified recombinant aminopeptidase B was not able to release d-amphetamine from LDX in vitro. The demonstration that aminopeptidase-like activity in red blood cell cytosol is responsible for the hydrolysis of LDX extends our understanding of the smooth and consistent systemic delivery of d-amphetamine by LDX and the long daily duration of efficacy of the drug in relieving the symptoms of attention-deficit/hyperactivity disorder.

Keywords: LDX; attention-deficit/hyperactivity disorder; hydrolysis; lisdexamfetamine; peptidase; prodrug.

Figures

Figure 1
Figure 1
LDX bioconversion to d-amphetamine in blood and blood cell extracts. Notes: Data for d-amphetamine are presented as the mean of four replicates (whole blood and negative control) or two replicates (other samples), with error bars showing SEM. Points without visible error bars have SEMs smaller than the height of the data point marker. Values for intact LDX remaining at 4 hours are expressed as percentages of the mean LDX concentration at 0 hours. Abbreviations: LDX, lisdexamfetamine dimesylate; SEM, standard error of the mean.
Figure 2
Figure 2
Effect of protease inhibitor cocktail and BNPP on d-amphetamine production from LDX in whole blood or cytosolic extract. Notes: Data for d-amphetamine are presented as the mean of two replicates, with error bars showing SEM. Points without visible error bars have SEMs smaller than the height of the data point marker. Values for intact LDX remaining at 4 hours are expressed as percentages of the mean LDX concentration at 0 hours. Abbreviations: BNPP, bis(4-nitrophenyl)phosphate; LDX, lisdexamfetamine dimesylate; SEM, standard error of the mean.
Figure 3
Figure 3
Effect of individual components of protease inhibitor cocktail on d-amphetamine production from LDX in red blood cell cytosolic extract. Notes: Data for d-amphetamine are presented as the mean of two replicates, with error bars showing SEM. Points without visible error bars have SEMs smaller than the height of the data point marker. Values for intact LDX remaining at 4 hours are expressed as percentages of the mean LDX concentration at 0 hours. Abbreviations: AEBSF, 4-(2-aminoethyl)benzenesulfonyl fluoride; EDTA, ethylenediaminetetra-acetic acid; LDX, lisdexamfetamine dimesylate; SEM, standard error of the mean.

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