The mechanism of lymphatic access of two cholesteryl ester transfer protein inhibitors (CP524,515 and CP532,623) and evaluation of their impact on lymph lipoprotein profiles.
OBJECTIVE
To explore the mechanism of lymphatic access of the CETP inhibitors (CETPi) CP524,515 and CP532,623 and probe their potential effect on lymph lipoprotein development.


METHODS
Lymphatic access mechanisms were examined via correlation of lymphatic drug transport profiles with drug affinity for lymph lipoproteins and drug solubility in representative combinations of lipoprotein lipids. The effects of the CETPi on lymph lipoprotein profiles were evaluated by ultracentrifugation and flow cytometry.


RESULTS
Both CETPi were highly lymphatically transported (22-28% of dose), and lymphatic transport was closely correlated with drug affinity for ex-vivo lymph lipoproteins or triglyceride emulsions and poorly related to solubility in mixtures of lipoprotein core and/or surface lipids. Both CETPi altered the kinetics of lymph lipid transport and decreased lymph lipid transport in chylomicrons.


CONCLUSIONS
Lymphatic transport of the CETPi appears to reflect high affinity for the interface of lymph lipoproteins rather than solubilisation in the lipoprotein core and confirms that triglyceride solubilities >50 mg/g are not necessarily a pre-requisite for lymphatic transport. The CETPi also led to changes to lipoprotein processing in the enterocyte including a reduction in lipid transport in chylomicrons. Changes to intestinal lipoprotein profiles may contribute to the changes in systemic lipoprotein levels seen during CETPi therapy.
Trevaskis
Natalie L
NL
Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Shanker
Ravi M
RM
Charman
William N
WN
Porter
Christopher J H
CJ
D000634:Aminoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D005434:Flow Cytometry; D008074:Lipoproteins / Q000378:metabolism*; D008196:Lymph / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D000634:Aminoquinolines; C550702:CP 524,515; C544076:CP 532,623; D002219:Carbamates; D053480:Cholesterol Ester Transfer Proteins; D008074:Lipoproteins; D011804:Quinolines