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

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ABSTRACT

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.

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Abbreviations

CETP:

cholesterol ester transfer protein

CM:

chylomicron

HDL:

high density lipoprotein

MTP:

microsomal TG transfer protein

PLTP:

phospholipid transfer protein

SMEDDS:

self micro-emulsifying drug delivery system

TBME:

tert-butyl methyl ether

TG:

triglyceride

VLDL:

very low density lipoprotein

LCT:

long chain triglyceride

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ACKNOWLEDGEMENTS

The authors thank Pfizer Global Research and Development (Groton, CT) for financial support and Michael Campbell and Daniel Gregg from the Centre for Drug Candidate Optimisation (CDCO), Monash Institute of Pharmaceutical Sciences, Parkville, Australia for the determination of Elog D.

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Authors and Affiliations

  1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia

    Natalie L. Trevaskis, Claire L. McEvoy, Michelle P. McIntosh, William N. Charman & Christopher J. H. Porter

  2. School of Veterinary Science, University of Melbourne, 250 Princess Highway, Werribee, VIC, 3030, Australia

    Glenn A. Edwards

  3. Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut, 06340, USA

    Ravi M. Shanker

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  1. Natalie L. Trevaskis
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  2. Claire L. McEvoy
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Correspondence to Christopher J. H. Porter.

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Trevaskis, N.L., McEvoy, C.L., McIntosh, M.P. et al. The Role of the Intestinal Lymphatics in the Absorption of Two Highly Lipophilic Cholesterol Ester Transfer Protein Inhibitors (CP524,515 and CP532,623). Pharm Res 27, 878–893 (2010). https://doi.org/10.1007/s11095-010-0083-0

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