Apomorphine and its esters: Differences in Caco-2 cell permeability and chylomicron affinity.
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.
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: nrupa.borkar@sund.ku.dk.
Nrupa
N
Borkar
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: zzchern@foxmail.com.
Zhizhong
Z
Chen
Bioneer: FARMA, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: lasse.saaby@sund.ku.dk.
Lasse
L
Saaby
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Bioneer: FARMA, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: anette.mullertz@sund.ku.dk.
Anette
A
Müllertz
Process Chemistry, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. Electronic address: aeh@lundbeck.com.
Anders E
AE
Håkansson
Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. Electronic address: cbec@lundbeck.com.
Christian
C
Schönbeck
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: mingshi.yang@sund.ku.dk.
Mingshi
M
Yang
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. Electronic address: rhol@lundbeck.com.
René
R
Holm
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: huiling.mu@sund.ku.dk.
Huiling
H
Mu
D001058:Apomorphine / Q000737:chemistry* / Q000378:metabolism*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002914:Chylomicrons / Q000737:chemistry* / Q000378:metabolism*; D004952:Esters / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007408:Intestinal Absorption / Q000502:physiology*; D010539:Permeability; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism
D002914:Chylomicrons; D004952:Esters; D011355:Prodrugs; D001058:Apomorphine
Apomorphine; Caco-2; Chylomicron affinity; Ester prodrug; Permeability; Stability