Apomorphine and its esters: Differences in Caco-2 cell permeability and chylomicron affinity

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

Research output: Contribution to journalJournal articleResearchpeer-review

16 Citations (Scopus)

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. Even though, the intact DLA transport is not favorable; the conversion of DLA to MLA is therefore, an important step for intestinal apomorphine absorption.

Original languageEnglish
JournalInternational Journal of Pharmaceutics
Volume509
Issue number1-2
Pages (from-to)499–506
Number of pages8
ISSN0378-5173
DOIs
Publication statusPublished - 6 Jun 2016

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