The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623)

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. CONCLUSION: 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.