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.

Pharmaceutical Research
Natalie L TrevaskisChristopher J H Porter

Abstract

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. 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. 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. 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 i...Continue Reading

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Citations

Feb 23, 2013·Pharmaceutical Research·Natalie L TrevaskisChristopher J H Porter
Apr 5, 2012·Journal of Lipid Research·Margaret R DiffenderferErnst J Schaefer
Jan 9, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Sifei HanChristopher J H Porter
Aug 26, 2014·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Claire L McEvoyChristopher J H Porter
May 23, 2013·Journal of Pharmaceutical Sciences·Suzanne M CaliphNatalie L Trevaskis
Oct 17, 2015·Nature Reviews. Drug Discovery·Natalie L TrevaskisChristopher J H Porter
Apr 20, 2016·Advanced Drug Delivery Reviews·Orlagh M FeeneyChristopher J H Porter
Jun 29, 2017·Nature Reviews. Gastroenterology & Hepatology·Jeremiah Bernier-Latmani, Tatiana V Petrova
Nov 12, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Edna F ChooRichard Voorman
Feb 7, 2013·Pharmacological Reviews·Hywel D WilliamsChristopher J H Porter
Feb 7, 2020·Current Pharmaceutical Design· HarshitaZiyaur Rahman
Jul 17, 2020·Frontiers in Physiology·Natalie L TrevaskisChristopher J H Porter
Mar 24, 2021·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Zahari VinarovPatrick Augustijns
Oct 21, 2010·Molecular Pharmaceutics·Natalie L TrevaskisChristopher J H Porter
Sep 1, 2021·Pharmaceutical Research·Sifei HanNatalie Trevaskis

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