Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2014 |
|---|---|
| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
|---|---|
| Enthalten in: |
Neuropsychiatric disease and treatment - 10(2014) vom: 24., Seite 2275-80 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Sharman, Johannah [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Attention-deficit/hyperactivity disorder |
|---|
| Anmerkungen: |
Date Completed 09.12.2014 Date Revised 30.09.2020 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.2147/NDT.S70382 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM24441985X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM24441985X | ||
| 003 | DE-627 | ||
| 005 | 20231224134648.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2014 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.2147/NDT.S70382 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0814.xml |
| 035 | |a (DE-627)NLM24441985X | ||
| 035 | |a (NLM)25489246 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Sharman, Johannah |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells |
| 264 | 1 | |c 2014 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 09.12.2014 | ||
| 500 | |a Date Revised 30.09.2020 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a LDX | |
| 650 | 4 | |a attention-deficit/hyperactivity disorder | |
| 650 | 4 | |a hydrolysis | |
| 650 | 4 | |a lisdexamfetamine | |
| 650 | 4 | |a peptidase | |
| 650 | 4 | |a prodrug | |
| 700 | 1 | |a Pennick, Michael |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Neuropsychiatric disease and treatment |d 2005 |g 10(2014) vom: 24., Seite 2275-80 |w (DE-627)NLM17652634X |x 1176-6328 |7 nnns |
| 773 | 1 | 8 | |g volume:10 |g year:2014 |g day:24 |g pages:2275-80 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.2147/NDT.S70382 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 10 |j 2014 |b 24 |h 2275-80 | ||