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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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