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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

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ABSTRACT

Purpose

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.

Conclusion

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.

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Abbreviations

CETP:

cholesterol ester transfer protein

CETPi:

CETP inhibitors

CM:

chylomicron

HDL:

high density lipoprotein

VLDL:

very low density lipoprotein

TRL:

TG rich lipoprotein

TG:

triglyceride

PL:

phospholipid

Ch:

cholesterol

CE:

cholesteryl ester

FA:

fatty acid

DPPC:

di-palmitoyl phosphatidylcholine

LCT:

long chain TG

MTP:

microsomal TG transfer protein

PLTP:

phospholipid transfer protein

FSC:

forward scatter

SSC:

side scatter

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ACKNOWLEDGEMENTS

Pfizer Global Research and Development is gratefully acknowledged for funding the program of work described in this manuscript.

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Correspondence to Christopher J. H. Porter.

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Trevaskis, N.L., Shanker, R.M., Charman, W.N. et al. 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. Pharm Res 27, 1949–1964 (2010). https://doi.org/10.1007/s11095-010-0199-2

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  • DOI: https://doi.org/10.1007/s11095-010-0199-2

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