Apomorphine and its esters

Differences in Caco-2 cell permeability and chylomicron affinity

Nrupa Nitin Borkar, Zhizhong Chen, Lasse Saaby, Anette Müllertz, Anders E. Håkansson, Jens Christian Sidney Schönbeck, Mingshi Yang, René Holm, Huiling Mu

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Oral delivery of apomorphine via prodrug principle may be a potential treatment for Parkinson’s disease. The purpose of this study was to investigate the transport and stability of apomorphine and its esters across Caco-2 cell monolayer and their affinity towards chylomicrons. Apomorphine, monolauroyl apomorphine (MLA) and dilauroyl apomorphine (DLA) were subjected to apical to basolateral (A-B) and basolateral to apical (B-A) transport across Caco-2 cell monolayer. The stability of these compounds was also assessed by incubation at intestinal pH and physiological pH with and without Caco-2 cells. Molecular dynamics (MD) simulations were performed to understand the stability of the esters on a molecular level. The affinity of the compounds towards plasma derived chylomicrons was assessed. The A-B transport of intact DLA was about 150 times lower than the transport of apomorphine. In contrast, MLA was highly unstable in the aqueous media leading to apomorphine appearance basolaterally. MD simulations possibly explained the differences in hydrolysis susceptibilities of DLA and MLA. The affinity of apomorphine diesters towards plasma derived chylomicrons provided an understanding of their potential lymphatic transport. The intact DLA transport is not favorable; therefore, the conversion of DLA to MLA is an important step for intestinal apomorphine absorption.
OriginalsprogEngelsk
TidsskriftInternational Journal of Pharmaceutics
Vol/bind509
Udgave nummer1-2
Sider (fra-til)499–506
ISSN0378-5173
DOI
StatusUdgivet - 2016
Udgivet eksterntJa

Citer dette

Borkar, Nrupa Nitin ; Chen, Zhizhong ; Saaby, Lasse ; Müllertz, Anette ; Håkansson, Anders E. ; Schönbeck, Jens Christian Sidney ; Yang, Mingshi ; Holm, René ; Mu, Huiling. / Apomorphine and its esters : Differences in Caco-2 cell permeability and chylomicron affinity. I: International Journal of Pharmaceutics. 2016 ; Bind 509, Nr. 1-2. s. 499–506.
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abstract = "Oral delivery of apomorphine via prodrug principle may be a potential treatment for Parkinson’s disease. The purpose of this study was to investigate the transport and stability of apomorphine and its esters across Caco-2 cell monolayer and their affinity towards chylomicrons. Apomorphine, monolauroyl apomorphine (MLA) and dilauroyl apomorphine (DLA) were subjected to apical to basolateral (A-B) and basolateral to apical (B-A) transport across Caco-2 cell monolayer. The stability of these compounds was also assessed by incubation at intestinal pH and physiological pH with and without Caco-2 cells. Molecular dynamics (MD) simulations were performed to understand the stability of the esters on a molecular level. The affinity of the compounds towards plasma derived chylomicrons was assessed. The A-B transport of intact DLA was about 150 times lower than the transport of apomorphine. In contrast, MLA was highly unstable in the aqueous media leading to apomorphine appearance basolaterally. MD simulations possibly explained the differences in hydrolysis susceptibilities of DLA and MLA. The affinity of apomorphine diesters towards plasma derived chylomicrons provided an understanding of their potential lymphatic transport. The intact DLA transport is not favorable; therefore, the conversion of DLA to MLA is an important step for intestinal apomorphine absorption.",
author = "Borkar, {Nrupa Nitin} and Zhizhong Chen and Lasse Saaby and Anette M{\"u}llertz and H{\aa}kansson, {Anders E.} and Sch{\"o}nbeck, {Jens Christian Sidney} and Mingshi Yang and Ren{\'e} Holm and Huiling Mu",
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Borkar, NN, Chen, Z, Saaby, L, Müllertz, A, Håkansson, AE, Schönbeck, JCS, Yang, M, Holm, R & Mu, H 2016, 'Apomorphine and its esters: Differences in Caco-2 cell permeability and chylomicron affinity', International Journal of Pharmaceutics, bind 509, nr. 1-2, s. 499–506. https://doi.org/10.1016/j.ijpharm.2016.06.010

Apomorphine and its esters : Differences in Caco-2 cell permeability and chylomicron affinity. / Borkar, Nrupa Nitin; Chen, Zhizhong; Saaby, Lasse; Müllertz, Anette; Håkansson, Anders E.; Schönbeck, Jens Christian Sidney; Yang, Mingshi; Holm, René; Mu, Huiling.

I: International Journal of Pharmaceutics, Bind 509, Nr. 1-2, 2016, s. 499–506.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Apomorphine and its esters

T2 - Differences in Caco-2 cell permeability and chylomicron affinity

AU - Borkar, Nrupa Nitin

AU - Chen, Zhizhong

AU - Saaby, Lasse

AU - Müllertz, Anette

AU - Håkansson, Anders E.

AU - Schönbeck, Jens Christian Sidney

AU - Yang, Mingshi

AU - Holm, René

AU - Mu, Huiling

PY - 2016

Y1 - 2016

N2 - Oral delivery of apomorphine via prodrug principle may be a potential treatment for Parkinson’s disease. The purpose of this study was to investigate the transport and stability of apomorphine and its esters across Caco-2 cell monolayer and their affinity towards chylomicrons. Apomorphine, monolauroyl apomorphine (MLA) and dilauroyl apomorphine (DLA) were subjected to apical to basolateral (A-B) and basolateral to apical (B-A) transport across Caco-2 cell monolayer. The stability of these compounds was also assessed by incubation at intestinal pH and physiological pH with and without Caco-2 cells. Molecular dynamics (MD) simulations were performed to understand the stability of the esters on a molecular level. The affinity of the compounds towards plasma derived chylomicrons was assessed. The A-B transport of intact DLA was about 150 times lower than the transport of apomorphine. In contrast, MLA was highly unstable in the aqueous media leading to apomorphine appearance basolaterally. MD simulations possibly explained the differences in hydrolysis susceptibilities of DLA and MLA. The affinity of apomorphine diesters towards plasma derived chylomicrons provided an understanding of their potential lymphatic transport. The intact DLA transport is not favorable; therefore, the conversion of DLA to MLA is an important step for intestinal apomorphine absorption.

AB - Oral delivery of apomorphine via prodrug principle may be a potential treatment for Parkinson’s disease. The purpose of this study was to investigate the transport and stability of apomorphine and its esters across Caco-2 cell monolayer and their affinity towards chylomicrons. Apomorphine, monolauroyl apomorphine (MLA) and dilauroyl apomorphine (DLA) were subjected to apical to basolateral (A-B) and basolateral to apical (B-A) transport across Caco-2 cell monolayer. The stability of these compounds was also assessed by incubation at intestinal pH and physiological pH with and without Caco-2 cells. Molecular dynamics (MD) simulations were performed to understand the stability of the esters on a molecular level. The affinity of the compounds towards plasma derived chylomicrons was assessed. The A-B transport of intact DLA was about 150 times lower than the transport of apomorphine. In contrast, MLA was highly unstable in the aqueous media leading to apomorphine appearance basolaterally. MD simulations possibly explained the differences in hydrolysis susceptibilities of DLA and MLA. The affinity of apomorphine diesters towards plasma derived chylomicrons provided an understanding of their potential lymphatic transport. The intact DLA transport is not favorable; therefore, the conversion of DLA to MLA is an important step for intestinal apomorphine absorption.

U2 - 10.1016/j.ijpharm.2016.06.010

DO - 10.1016/j.ijpharm.2016.06.010

M3 - Journal article

VL - 509

SP - 499

EP - 506

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

IS - 1-2

ER -