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פותח על ידי קלירמאש פתרונות בע"מ -
The oral absorption of phospholipid prodrugs: In vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration
Year:
2008
Source of publication :
Journal of Controlled Release
Authors :
אלמן, ענת
;
.
Volume :
126
Co-Authors:
Dahan, A., Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Jerusalem, Israel
Duvdevani, R., D-Pharm LTD, Rehovot, Israel
Shapiro, I., D-Pharm LTD, Rehovot, Israel
Elmann, A., D-Pharm LTD, Rehovot, Israel
Finkelstein, E., D-Pharm LTD, Rehovot, Israel
Hoffman, A., Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Jerusalem, Israel
Facilitators :
From page:
1
To page:
9
(
Total pages:
9
)
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. © 2007 Elsevier B.V. All rights reserved.
Note:
Related Files :
Animals
drug absorption
Drug Stability
enzymes
Food Products
Male
mice
Molecular structure
עוד תגיות
תוכן קשור
More details
DOI :
10.1016/j.jconrel.2007.10.025
Article number:
Affiliations:
Database:
סקופוס
Publication Type:
מאמר
;
.
Language:
אנגלית
Editors' remarks:
ID:
26022
Last updated date:
02/03/2022 17:27
Creation date:
17/04/2018 00:19
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Scientific Publication
The oral absorption of phospholipid prodrugs: In vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration
126
Dahan, A., Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Jerusalem, Israel
Duvdevani, R., D-Pharm LTD, Rehovot, Israel
Shapiro, I., D-Pharm LTD, Rehovot, Israel
Elmann, A., D-Pharm LTD, Rehovot, Israel
Finkelstein, E., D-Pharm LTD, Rehovot, Israel
Hoffman, A., Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Jerusalem, Israel
The oral absorption of phospholipid prodrugs: In vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration
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. © 2007 Elsevier B.V. All rights reserved.
Scientific Publication
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