The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623).
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.
Trevaskis
Natalie L
NL
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
McEvoy
Claire L
CL
McIntosh
Michelle P
MP
Edwards
Glenn A
GA
Shanker
Ravi M
RM
Charman
William N
WN
Porter
Christopher J H
CJ
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
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