The oral absorption of phospholipid prodrugs: In vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration

Arik Dahan, Revital Duvdevani, Israel Shapiro, Anat Elmann, Elena Finkelstein, Amnon Hoffman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

The purpose of this study was to evaluate the oral absorption characteristics of a phospholipid-drug conjugate, comprising direct conjugation between the lecithin and the drug moiety through the sn-2 position. We investigated the mechanisms involved with the trafficking of this conjugate following oral administration in the gastrointestinal (GI) lumen, within the enterocyte and further. A phospholipid-valproic acid conjugate (DP-VPA) was utilized as a model molecule. The oral absorption of this conjugate in rats was investigated following administration in long (LCT) vs. medium (MCT) chain triglyceride formulations, and in the postprandial vs. fasted state. Oral administration within the LCT solution caused more than a 3-fold increase in DP-VPA bioavailability in comparison to the MCT solution. Moreover, a significant food effect was evident for DP-VPA. Hence, we evaluated the lymphatic transport of DP-VPA in mesenteric lymph duct cannulated freely moving rats. Sixty percent of the absorbed DP-VPA was associated with lymphatic transport. Similar DP-VPA absorption was obtained in secretory type II PLA2 knockout mice (C57BL/6) and in control mice (BALB/c). Moreover, nil DP-VPA degradation in serum and very low (4.8%) degradation by bee venom PLA2 in vitro were obtained. In conclusion, direct conjugation between the drug and the phospholipid produces a complex having unique absorption properties that include: (1) a stable complex that does not undergo degradation in the GI tract; (2) permeation through the gut wall and entering intact to the enterocyte; and (3) association with chylomicron in the enterocyte and reaching the systemic circulation via the lymphatic route. These unique properties may be of interest in drug delivery.

Original languageAmerican English
Pages (from-to)1-9
Number of pages9
JournalJournal of Controlled Release
Volume126
Issue number1
DOIs
StatePublished - 18 Feb 2008

Keywords

  • Drug delivery
  • Food effect
  • Lymphatic transport
  • Oral prodrug
  • Pharmacokinetics
  • Phospholipase A
  • Phospholipid-drug conjugate
  • Valproic acid

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