The role of molecular physicochemical properties and apolipoproteins in association of drugs with triglyceride-rich lipoproteins: in-silico prediction of uptake by chylomicrons.
OBJECTIVE
The uptake of drugs by chylomicrons is a key element in both intestinal lymphatic transport and postprandial alterations in the disposition profile of lipophilic drugs. The aim of this article was to elucidate the factors that affect this phenomenon.


METHODS
The degree of association of 22 model lipophilic molecules with rat chylomicrons was assessed and correlated in silico with calculated physicochemical properties. The in-silico model was then validated using an external set of molecules. The uptake by chylomicrons was also compared to the association with a marketed artificial emulsion.


RESULTS
The most important physicochemical property that affects the affinity to chylomicrons was found to be LogD7.4; however, a multiparameter model was required to describe properly the uptake process. The in-silico model (R2Y=0.91, R2X=0.91 and Q2=0.82) that was created using a combination of eight molecular descriptors enabled successful prediction of the affinity of the external set of molecules to chylomicrons. The association with the artificial emulsion was statistically different from the uptake by chylomicrons for four (out of nine) molecules.


CONCLUSIONS
The association of drugs with chylomicrons is a complex process, which involves the lipophilic core as well as surface apoproteins. The in-silico model based on multiple physicochemical properties of the drugs is able to predict successfully the degree of association with chylomicrons.
Gershkovich
Pavel
P
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Fanous
Joseph
J
Qadri
Bashir
B
Yacovan
Avihai
A
Amselem
Shimon
S
Hoffman
Amnon
A
D000818:Animals; D001053:Apolipoproteins / Q000737:chemistry*; D055598:Chemical Phenomena; D002914:Chylomicrons / Q000737:chemistry / Q000493:pharmacokinetics; D003198:Computer Simulation; D004655:Emulsions; D006863:Hydrogen-Ion Concentration; D008074:Lipoproteins / Q000737:chemistry*; D008297:Male; D008954:Models, Biological; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D014280:Triglycerides / Q000737:chemistry*
D001053:Apolipoproteins; D002914:Chylomicrons; D004655:Emulsions; D008074:Lipoproteins; D004364:Pharmaceutical Preparations; D014280:Triglycerides