The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623)
- Pharm Res. 2010 May;27(5):878-93. doi: 10.1007/s11095-010-0083-0.
- 1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Purpose: 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.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: CETPResearch Areas: Metabolic Disease