Enhanced oral bioavailability of 3,3 '-diindolylmethane administered in a self-microemulsifying drug delivery system (SMEDDS)

3,39-diindolylmethane (DIM) is a stable, water-insoluble indole that demonstrates chemopreventive activity in several preclinical models for human cancer. Although clinical data have shown that the safety profile of absorption-enhanced, microencapsulated DIM is consistent with its use in cancer chemoprevention in humans, the in vivo biological activity of DIM is limited by poor solubility and very low oral bioavailability. Self-Microemulsifying Drug Delivery Systems (SMEDDS) provide a novel approach to improving the systemic delivery of lipophilic agents with poor oral bioavailability. Lipid-based SMEDDS formulations form oil-in-water microemulsions in aqueous gastric fluid; the microemulsions increase drug solubility and improve systemic absorption. The present study was performed to determine if the oral bioavailability of DIM and its levels in the prostate are increased by administration in a DIM-specific SMEDDS formulation. Fifteen male CD rats per group received a single oral (gavage) dose of either a microencapsulated DIM formulation (BR-DIM ® , BioResponse) or a SMEDDS formulation of DIM (BR-9001, BioResponse). Both groups received a DIM-equivalent dose of 30 mg/kg. Gavage administration of each DIM formulation was immediately followed by a second gavage dose of saline to provide uniform intragastric emulsification of BR-9001 and suspension of BR-DIM. Cohorts of three rats per group were bled at time 0 (pre-dose) and at 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 8.0, and 24 hours post-dosing; each rat was bled twice. After the second bleed, each rat was euthanized and its prostate was collected. Plasma samples and weighed samples of prostate were extracted and analyzed for DIM content by LC-MS/MS, and plasma pharmacokinetics parameters were calculated. The oral bioavailability of DIM was substantially greater in the SMEDDS BR-9001 formulation than in the BR-DIM formulation: at the Tmax (30 min), mean plasma DIM levels in rats receiving the SMEDDS formulation were u003e400% of mean plasma DIM levels in rats dosed with microencapsulated BR-DIM. For four hours after dosing, plasma DIM levels in SMEDDS-treated rats remained above plasma DIM levels in rats treated with microencapsulated DIM; the AUC for the SMEDDS formulation of DIM was approximately twice that for the microencapsulated DIM formulation. Similarly, at 2, 4, and 6 hours post-dosing, mean prostate DIM levels in rats receiving the SMEDDS formulation were approximately 200% of mean prostate DIM levels in rats receiving microencapsulated BR-DIM. These data demonstrate that plasma and prostate levels of DIM can be increased by using the BR-9001 SMEDDS formulation of DIM. Because the chemopreventive efficacy of DIM appears to be limited by poor oral bioavailability, the use of SMEDDS formulation technology may increase the efficacy of DIM for cancer chemoprevention. [HHSN261201500024I from the NCI, DHHS.] Citation Format: William D. Johnson, Miguel Muzzio, Thomas L. Horn, Michael A. Zeligs, Elizabeth R. Glaze, David L. McCormick. Enhanced oral bioavailability of 3,39-diindolylmethane administered in a self-microemulsifying drug delivery system (SMEDDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4931.