title: The influence of intestinal lymphatic transport on the systemic exposure and brain deposition of a novel highly lipophilic compound with structural similarity to cholesterol.
abstract: OBJECTIVE
  To assess the role of intestinal lymphatic transport in the oral bioavailability and brain deposition of a highly lipophilic, centrally acting drug candidate (Org 49209) in comparison to cholesterol, a close structural analogue.
  
  
  METHODS
  The intestinal lymphatic transport of Org 49209 and cholesterol was assessed in lymph-cannulated anaesthetised rats and total bioavailability evaluated in non-lymph-cannulated animals. Parallel groups were employed to examine the brain deposition of Org 49209 after intraduodenal and intraperitoneal administrations.
  
  
  RESULTS
  The contribution of intestinal lymphatic transport to total bioavailability was similar for Org 49209 and cholesterol (approximately 40% of the absorbed dose). However, the oral bioavailability of Org 49209 was significantly (fourfold) lower than cholesterol. Brain deposition of Org 49209 was similar after intraduodenal and intraperitoneal administration. Systemic exposure, however, was higher after intraduodenal administration and brain-to-plasma ratios were therefore reduced.
  
  
  CONCLUSIONS
  The oral bioavailability of Org 49209 was significantly lower than that of its structural analogue cholesterol; however, intestinal lymphatic transport played a similar role in oral bioavailability for both compounds. Brain to plasma ratios were lower after intraduodenal versus intraperitoneal administration, suggesting that drug association with intestinal lymph lipoproteins may limit central nervous system access for highly lipophilic drugs.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Vic, Australia.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Caliph
authors.forename: Fried W
authors.initials: FW
authors.lastname: Faassen
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism; D008196:Lymph / Q000378:metabolism*; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000378:metabolism; D009654:Norsteroids / Q000378:metabolism / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D008074:Lipoproteins; D009654:Norsteroids; C000598173:Org 49209; D016202:N-Methylaspartate; D002784:Cholesterol
keywords: brain deposition; drug absorption; lipid-based formulation; lymphatic transport; poorly water-soluble drugs