Uptake of lipophilic drugs by plasma derived isolated chylomicrons: Linear correlation with intestinal lymphatic bioavailability

Pavel Gershkovich, Amnon Hoffman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

Abstract

Association of a drug with chylomicrons in the enterocyte is an essential step in the lymphatic absorption pathway. In this article, the uptake of lipophilic compounds by chylomicrons ex vivo was compared to the corresponding intestinal lymphatic bioavailability reported in rats in order to elucidate the degree of correlation and to evaluate the utilization of this correlation as a predictive measurement of the lymphatic bioavailability potential of lipophilic drugs. Nine lipophilic compounds (Vitamin D3, Vitamin E, halofantrine, probucol, diazepam, testosterone, cyclosporin A, benzo[a]pyrene and p,p′-DDT) at a concentration of 1.75 × 10-6 M were incubated for 1 h with chylomicron emulsion separated from rat blood. A strong linear correlation was found between the degree of association of compounds with chylomicrons ex vivo and the lymphatic transport reported in rats (r 2 = 0.94, P < 0.0001), whereas log P and solubility in long chain triglycerides showed only moderate correlation with lymphatic bioavailability. The linear correlation between the degree of uptake of compounds by isolated chylomicrons and intestinal lymphatic transport suggests that the two processes are governed by similar factors. Thus, the degree of association of lipophilic compounds with isolated chylomicrons can be used as a simple screening model for estimation of intestinal lymphatic transport potential of drug molecules. This approach is important in view of the practical difficulties in direct determination of the lymphatic bioavailability in vivo.

Original languageAmerican English
Pages (from-to)394-404
Number of pages11
JournalEuropean Journal of Pharmaceutical Sciences
Volume26
Issue number5
DOIs
StatePublished - Dec 2005

Bibliographical note

Funding Information:
This paper is a part of Pavel Gershkovich PhD dissertation. This study was supported by Israeli Consortium of Pharmalogica. We would like to thank Anna Elgart for her excellent technical assistance and Dr. Josh Backon for constructive comments. Prof. Amnon Hoffman is affiliated with the David R. Bloom Center for Pharmacy at The Hebrew University of Jerusalem.

Keywords

  • Absorption
  • Chylomicrons
  • Ex vivo
  • Lipophilic drugs
  • Lymphatic transport
  • log P

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