Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells

Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells

Johannah Sharman, Michael Pennick Shire, Basingstoke, UK 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 link...

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Autores principales: Sharman J, Pennick M
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2014
Materias:
Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Neurology. Diseases of the nervous system
RC346-429
Acceso en línea:https://doaj.org/article/d3386f703dc14cf3962bea08b8cf1409
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spelling oai:doaj.org-article:d3386f703dc14cf3962bea08b8cf14092021-12-02T08:06:57ZLisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells1178-2021https://doaj.org/article/d3386f703dc14cf3962bea08b8cf14092014-11-01T00:00:00Zhttp://www.dovepress.com/lisdexamfetamine-prodrug-activation-by-peptidase-mediated-hydrolysis-i-peer-reviewed-article-NDThttps://doaj.org/toc/1178-2021 Johannah Sharman, Michael Pennick Shire, Basingstoke, UK 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: lisdexamfetamine, LDX, prodrug, peptidase, hydrolysis, attention-deficit/hyperactivity disorderSharman JPennick MDove Medical PressarticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENNeuropsychiatric Disease and Treatment, Vol 2014, Iss default, Pp 2275-2280 (2014)
institution DOAJ
collection DOAJ
language EN
topic Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Neurology. Diseases of the nervous system
RC346-429
spellingShingle Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Neurology. Diseases of the nervous system
RC346-429
Sharman J
Pennick M
Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells
description Johannah Sharman, Michael Pennick Shire, Basingstoke, UK 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: lisdexamfetamine, LDX, prodrug, peptidase, hydrolysis, attention-deficit/hyperactivity disorder
format article
author Sharman J
Pennick M
author_facet Sharman J
Pennick M
author_sort Sharman J
title Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells
title_short Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells
title_full Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells
title_fullStr Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells
title_full_unstemmed Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells
title_sort lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells
publisher Dove Medical Press
publishDate 2014
url https://doaj.org/article/d3386f703dc14cf3962bea08b8cf1409
work_keys_str_mv AT sharmanj lisdexamfetamineprodrugactivationbypeptidasemediatedhydrolysisinthecytosolofnbspredbloodcells
AT pennickm lisdexamfetamineprodrugactivationbypeptidasemediatedhydrolysisinthecytosolofnbspredbloodcells
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