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

Dahan, Arik; Duvdevani, Revital; Shapiro, I.; Elmann, Anat; Finkelstein, Elena; Hoffman, Amnon

doi:10.1016/j.jconrel.2007.10.025

Cited by 72 publications

(62 citation statements)

References 42 publications

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“…Mechanisms by which increased drug absorption can occur include slowing of gastric emptying, enhancement of gastrointestinal dissolution or solubilization, protection from intestinal degradation, and stimulation of lymphatic drug transport (Charman et al, 1997;Wasan, 2001;Grove et al, 2007;Porter et al, 2007;Dahan et al, 2008). In the current study, the oral bioavailability of MU in fed animals increased 35-fold compared with bioavailability in fasted animals.…”

Section: Discussionmentioning

confidence: 99%

“…al., 1986); therefore, increases in postprandial absorption alone are unlikely to lead to significant increases in bioavailability without attendant effects on first-pass metabolism. In this regard, MU is highly lipophilic (437 mg ⅐ ml Ϫ1 solubility in soybean oil and calculated log P 8.73), and for compounds of this type, access to the systemic circulation after oral absorption may occur via the lymphatic system rather than by transport into portal blood (Charman and Stella, 1986;Wasan, 2001;Holm et al, 2002;Hauss, 2007;Dahan et al, 2008). Lymphatic drug transport is typically increased after postprandial administration because the lipids in food stimulate the synthesis of lymph lipoproteins, which in turn act as carriers for lymphatically transported drugs (Charman and Stella, 1991;Porter and Charman, 2001a;Wasan, 2001;Holm et al, 2002;Hauss, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid after Oral Administration of MU

White¹,

Nguyen²,

Charman³

et al. 2009

J Pharmacol Exp Ther

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The contribution of lymphatic transport to the oral bioavailability of methylnortestosterone (M) after oral administration of the lipophilic prodrug methylnortestosterone undecanoate (MU) has been evaluated, and the sensitivity of lymphatic MU transport to lymphatic lipid transport has been investigated. M and MU were administered intravenously and orally to greyhound dogs to determine absolute bioavailability after oral dosing of MU. MU was also administered orally with differing quantities of food (lipid) to lymph duct-cannulated greyhound dogs to investigate the relative roles of lymph versus blood transport on M bioavailability and the effect of lipid load on systemic exposure. The relationship between lymphatic lipid and MU transport was further investigated in anesthetized rats. The oral bioavailability of M after administration of MU was found to be highly dependent on coadministration of food, and the bioavailability of M increased approximately 700% in fed versus fasted animals. In both cases, lymph diversion resulted in negligible systemic exposure of M, indicating almost complete dependence on lymphatic transport of MU for systemic exposure of M. Lymphatic transport of MU was even more highly dependent on the quantity of coadministered lipid and increased more than 50-fold with increasing lipid load. Therefore, increasing the quantity of food or lipid coadministered with MU stimulated a significant increase in the lymphatic transport of MU and systemic exposure of M. The lipid sensitivity of lymphatic transport of MU is significantly higher than previously observed for more metabolically stable compounds, suggesting a role for coadministered lipid in promoting avoidance of enterocyte-based cleavage of MU.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid after Oral Administration of MU

White¹,

Nguyen²,

Charman³

et al. 2009

J Pharmacol Exp Ther

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“…The absorption pattern of DP-VPA follows a unique pattern whereby the complex permeates through the gut wall and enters intact to the enterocyte. Then it associates itself with chylomicrons and reaches the systemic blood circulation via the lymphatic route (84).…”

Section: Rufinamide (Banzel ® ; Inovelon ® ) (23) Rufinamide (Rfm) (mentioning

confidence: 99%

An overview on antiepileptic drugs

2012

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Epilepsy is the most common chronic neurological disorder of the brain. For several decades different kinds of medications have been used to treat epilepsy. Even though many surgical advances has been made and implemented, medications remain the basis of treatment. The search for noble antiepileptic drugs (AEDs) with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. Additionally, drug resistance is an important clinical problem in epilepsy and is associated with an increased risk of morbidity and mortality. This review intends to present a comprehensive overview on AED in particular along with discussion on some aspects of associated drug resistance and combination therapy.

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“…In a well-designed experiment, Dahan et al (2008) have carefully evaluated the oral absorption pattern of phospholipid prodrugs using phospholipid-valproic acid conjugate as a model substrate. Lecithin served as an ideal agent for valproic acid conjugation and experimental conditions included fasted and postprandial conditions with both medium chain and long chain triglyceride formulations.…”

Section: Phospholipid Prodrugsmentioning

confidence: 99%

The rationality for using prodrug approach in drug discovery programs for new xenobiotics: opportunities and challenges

Srinivas¹

2011

Eur J Drug Metab Pharmacokinet

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The concept of prodrugs has been successfully executed for life cycle management options of several approved drugs and drugs in development. In addition to imparting ideal biopharmaceutical properties, such as solubility, permeability and lipophilicity, some prodrug concepts have also enabled site-specific drug delivery, prolonged the duration of therapeutic effect and improved therapeutic index. The strategic inclusion of prodrug concept during drug discovery and early development process brings in some unique challenges. The communication provides balanced perspectives on the rational use and challenges of prodrug concept during the drug discovery and development process.

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

Cited by 72 publications

References 42 publications

Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid after Oral Administration of MU

Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid after Oral Administration of MU

An overview on antiepileptic drugs

The rationality for using prodrug approach in drug discovery programs for new xenobiotics: opportunities and challenges

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