Efficacious Intestinal Permeation Enhancement Induced by the Sodium Salt of 10-undecylenic Acid, A Medium Chain Fatty Acid Derivative

Abstract

ABSTRACT. 10-undecylenic acid (UA) is an OTC antifungal therapy and a nutritional supplement. It is an unsaturated medium chain fatty acid (MCFA) derivative, so our hypothesis was that its 11-mer sodium salt, uC 11 , would improve intestinal permeation similar to the established enhancer, sodium caprate (C 10 ), but without the toxicity of the parent saturated MCFA, decylenic acid (C 11 ). MTT assay and high-content screening (HCS) confirmed a cytotoxicity ranking in Caco-2 cells: C 11 >C 10 =uC 11 . Five to ten millimolars of the three agents reduced TEER and increased the Papp of [ 14 C]-mannitol across Caco-2 monolayers and rat intestinal mucosae, a concentration that matched increases in plasma membrane permeability seen in HCS. Although C 11 was the most efficacious enhancer in vitro, it damaged monolayers and tissue mucosae more than the other two agents at similar concentrations and exposure times and was therefore not pursued further. Rat jejunal and colonic in situ intestinal instillations of 100 mM C 10 or uC 11 with FITC-dextran 4000 (FD4) solutions yielded comparable regional enhancement ratios of~10 and 30%, respectively, for each agent with acceptable tissue histology. Mini-tablets of uC 11 and FD4 however delivered more FD4 compared to C 10 -FD-4 mini-tablets in both regions, as reflected by a statistically higher AUC, and with no evidence of membrane perturbation. The unsaturated bond in uC 11 therefore confers a reduction in lipophilicity and cytotoxicity compared to C 11 , and the resulting permeation enhancement is on a par with or superior to that of C 10 , a key component of formulations in current phase II oral peptide clinical trials.

Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro

“…intestinal permeation enhancer, however, recently uC 11 was shown to have similar efficacy in isolated rat colon and in in situ rat intestinal instillations, whereby the P app of FD-4 was increased several fold by both C 10 and uC 11 (23). These enhancers reduced colonic TEER values in accordance with previously published results (21).…”

“…The cytotoxicity data and histology confirm that any impact in the tissue mounted on the Ussing chambers are most likely from the MCFA, which were previously shown to have significant cytotoxicity in the MTT assay at 1 and 24 h exposures in Caco-2 cells (23). Mucosa histology also shows a perturbation of the intestinal and colonic epithelia, comparable to previous studies investigating these MCFA (23). Repair is possible following transient mild damage to the tissue in intact in situ rat intestinal instillations using similar enhancers, which caused similar initial perturbation (38).…”

“…A previous study found no potential for IPP and VPP to induce cytotoxicity or clastogenicity in Chinese hamster lung cells (37). The cytotoxicity data and histology confirm that any impact in the tissue mounted on the Ussing chambers are most likely from the MCFA, which were previously shown to have significant cytotoxicity in the MTT assay at 1 and 24 h exposures in Caco-2 cells (23). Mucosa histology also shows a perturbation of the intestinal and colonic epithelia, comparable to previous studies investigating these MCFA (23).…”

“…One of the lead MCFA in clinical trials, capric acid, is found in mM concentrations in dairy products, and its sodium salt (C 10 ) has shown extensive enhancement effects in vitro and in vivo (22). Recently, an over-the-counter nutritional supplement and antifungal agent, the sodium salt of 10-undecylenic acid (uC 11 ), demonstrated similar permeation enhancement effects to C 10 in vitro using isolated rat intestinal mucosae and in vivo in rat intestinal loop instillations (23). However, applying such enhancers to foodderived peptides in oral formulations has not been attempted before.…”

An Involvement of PI3‐K/Akt Activation and Inhibition of AIF Translocation in Neuroprotective Effects of Undecylenic Acid (UDA) Against Pro‐Apoptotic Factors‐Induced Cell Death in Human Neuroblastoma SH‐SY5Y Cells

“…It is produced by the vacuum distillation of castor bean oil, via the pyrolysis of ricinoleic acid and has been used for several years as the active ingredient in many topical over‐the‐counter antifungal preparations and a nutritional supplement for maintaining a healthy balance of intestinal and vaginal microbial flora [Monograph, ; Van der Steen and Stevens, ]. On the basis of observations of a continued marketing of UDA in the USA as a nutritional supplement over many years, UDA is thought to be a quite safe drug in humans [Monograph, ; Brayden and Walsh, ]. Since UDA is a water insoluble compound, its vinyl ester derivatives have been synthesized to enhance its water solubility.…”