title: The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623).
abstract: OBJECTIVE
  To evaluate the potential role of intestinal lymphatic transport in the absorption and oral bioavailability of members of an emerging class of anti-atherosclerosis drugs (CETP inhibitors). CP524,515 and CP532,623 are structurally related with eLogD(7.4) >5; however, only CP524,515 (and not CP532,623) had sufficient solubility (>50 mg/g) in long-chain triglyceride (LCT) to be considered likely to be lymphatically transported.
  
  
  METHODS
  CP524,515 and CP532,623 were administered intravenously and orally to fasted or fed lymph-cannulated or non-cannulated dogs. Oral bioavailability and lymphatic transport of drug (and triglyceride) was subsequently quantified.
  
  
  RESULTS
  Both CETP inhibitors were substantially transported into the lymphatic system (>25% dose) in fed and fasted dogs. Food enhanced oral bioavailability (from 45 to 83% and 44 to 58% for CP524,515 and CP532,623, respectively) and the proportion of the absorbed dose transported via the lymph (from 61 to 86% and from 68 to 83%, respectively). Lymphatic triglyceride transport was significantly lower in fed dogs administered CP532,623.
  
  
  CONCLUSIONS
  Intestinal lymphatic transport is the major absorption pathway for CP524,515 and CP532,623, suggesting that a LCT solubility >50 mg/g is not an absolute requirement for lymphatic transport. The effect of CP532,623 on intestinal lipid transport may suggest a role in the activity/toxicity profiles of CETP inhibitors.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Trevaskis
authors.forename: Claire L
authors.initials: CL
authors.lastname: McEvoy
authors.forename: Michelle P
authors.initials: MP
authors.lastname: McIntosh
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Edwards
authors.forename: Ravi M
authors.initials: RM
authors.lastname: Shanker
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D000284:Administration, Oral; D000634:Aminoquinolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002219:Carbamates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D018565:Food-Drug Interactions; D006207:Half-Life; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008970:Molecular Weight; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D014280:Triglycerides / Q000737:chemistry
chemical_list: D000634:Aminoquinolines; D000924:Anticholesteremic Agents; C550702:CP 524,515; C544076:CP 532,623; D002219:Carbamates; D053480:Cholesterol Ester Transfer Proteins; D008055:Lipids; D011804:Quinolines; D014280:Triglycerides