Lymphatic transport of methylnortestosterone undecanoate (MU) and the bioavailability of methylnortestosterone are highly sensitive to the mass of co-administered lipid following oral administration of MU

The contribution of lymphatic transport to the oral bioavailability of methylnortestosterone (M) following oral administration of the lipophilic prodrug methylnortestosterone undecanoate (MU) has been evaluated and the sensitivity of lymphatic MU transport to lymphatic lipid transport investigated. M and MU were administered intravenously and orally to greyhound dogs to determine absolute bioavailability following 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 vs 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 co-administration of food and the bioavailability of M increased approximately 700% in fed vs 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 co-administered lipid and increased over 50-fold with increasing lipid load. Increasing the quantity of food or lipid co-administered with MU therefore 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 co-administered lipid in promoting avoidance of enterocyte based cleavage of MU. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on August 20, 2009 as DOI: 10.1124/jpet.109.154542 at A PE T Jornals on O cber 9, 2017 jpet.asjournals.org D ow nladed from