Role of the Intestinal Lymphatics in the Absorption of Two Highly Lipophilic Cholesterol Ester Transfer Protein Inhibitors (CP524,515 and CP532,623)

• Published in: Pharmaceutical research Vol. 27; no. 5; pp. 878 - 893
• Main Authors: Trevaskis, Natalie L, McEvoy, Claire L, McIntosh, Michelle P, Edwards, Glenn A, Shanker, Ravi M, Charman, William N, Porter, Christopher J. H
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.05.2010; Springer US; Springer; Springer Nature B.V
• Subjects: Administration, Oral; Aminoquinolines - administration & dosage; Aminoquinolines - chemistry; Aminoquinolines - pharmacokinetics; Animals; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - chemistry; Anticholesteremic Agents - pharmacokinetics; Area Under Curve; Atherosclerosis; Bioavailability; Biochemistry; Biological and medical sciences; Biological Availability; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Carbamates - administration & dosage; Carbamates - chemistry; Carbamates - pharmacokinetics; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Chromatography, High Pressure Liquid; Dogs; Food-Drug Interactions; General pharmacology; Half-Life; Injections, Intravenous; Intestinal Absorption - physiology; Intestines - metabolism; Kinetics; Large intestine; Lipids - chemistry; Lymphatic System - metabolism; Male; Mass Spectrometry; Medical Law; Medical sciences; Molecular Weight; Pharmaceutical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Quinolines - administration & dosage; Quinolines - chemistry; Quinolines - pharmacokinetics; Research Paper; Small intestine; Solubility; Triglycerides - chemistry; CETP inhibitor; lymphatic transport; intestine; absorption; torcetrapib; Protein inhibitor; Lymphatic system; Pharmaceutical technology; Gut; Lymphatic; Cholesterol; Ester; Absorption; Torcetrapib; Pharmacokinetics; Transport; Antilipemic agent
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-010-0083-0

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 eLogD₇.₄ >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.