The role of molecular physicochemical properties and apolipoproteins in association of drugs with triglyceride-rich lipoproteins: In-silico prediction of uptake by chylomicrons

Pavel Gershkovich, Joseph Fanous, Bashir Qadri, Avihai Yacovan, Shimon Amselem, Amnon Hoffman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Objectives 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. Key findings The most important physicochemical property that affects the affinity to chylomicrons was found to be LogD74; 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.

Original languageAmerican English
Pages (from-to)31-39
Number of pages9
JournalJournal of Pharmacy and Pharmacology
Volume61
Issue number1
DOIs
StatePublished - Jan 2009

Keywords

  • Chylomicrons
  • In-silico model
  • Lipophilic drugs
  • Lipoproteins
  • Physicochemical properties

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