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.

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.

Oral bioavailability assessment and intestinal lymphatic transport of Org 45697 and Org 46035, two highly lipophilic novel immunomodulator analogues.

Org 45697 (MW 600.7, clogP 7.92, soybean oil solubility 50 mg/g) and Org 46035 (MW 601.6, clog P 8.46, soybean oil solubility 40 mg/g) are two poorly water soluble (<0.1 microg/ml), highly lipophilic drug candidates with immunomodulator activity and highly analogous chemical structures. After oral administration to conscious ambulatory rats in an aqueous-based methylcellulose/Tween 80 suspension, the bioavailability of both compounds was low (< 2% of administered dose). However, bioavailability was significantly increased (> 5 fold) after oral administration in a long chain triglyceride lipid (olive oil) formulation. Subsequent studies have explored the potential for solubilising formulations, including lipid-based formulations, to enhance the oral bioavailability of Org 45697 and Org 46035 and secondly to explore the potential contribution of intestinal lymphatic transport to intestinal absorption. The experimental data show that solubilising formulations may provide for significant increases in oral bioavailability for Org 45697 and Org 46035 and that after co-administration with lipid, 35-50% of the absorbed dose may be transported to the systemic circulation via the intestinal lymph. Interestingly, the lymphatic transport of the less lipid soluble analogue, Org 46035 was approximately 40% lower than that of Org 45697 suggesting that relatively subtle differences in lipid solubility can have significant impact on the extent of lymphatic transport.