title: 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.
abstract: 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.
authors.affiliation: Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University,Parkville, Victoria, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Gary
authors.initials: G
authors.lastname: Nguyen
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Edwards
authors.forename: W A Fried
authors.initials: WA
authors.lastname: Faassen
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004041:Dietary Fats / Q000494:pharmacology*; D004285:Dogs; D020895:Enterocytes / Q000378:metabolism; D004963:Estrenes / Q000493:pharmacokinetics*; D005215:Fasting / Q000378:metabolism; D007275:Injections, Intravenous; D008196:Lymph / Q000378:metabolism; D008208:Lymphatic System / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010616:Phenanthrenes / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000962:Antimalarials; D004041:Dietary Fats; D004963:Estrenes; D010616:Phenanthrenes; D014280:Triglycerides; C545123:methylnortestosterone undecanoate; D009277:Nandrolone; C073330:methylestrenolone; C023768:halofantrine