title: Oral bioavailability assessment and intestinal lymphatic transport of Org 45697 and Org 46035, two highly lipophilic novel immunomodulator analogues.
abstract: 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.
authors.affiliation: Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Caliph
authors.forename: W A Fried
authors.initials: WA
authors.lastname: Faassen
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Vogel
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D007155:Immunologic Factors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D000069463:Olive Oil; D010938:Plant Oils / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D007155:Immunologic Factors; D000069463:Olive Oil; C545056:Org 45697; C545057:Org 46035; D010938:Plant Oils; D011136:Polysorbates; D011743:Pyrimidines; D013501:Surface-Active Agents; D007930:Leucine