Skip to main content
SpringerLink
Log in

Intestinal Lymphatic Transport Enhances the Post-Prandial Oral Bioavailability of a Novel Cannabinoid Receptor Agonist Via Avoidance of First-Pass Metabolism

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs.

Methods

Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13.

Results

Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3–4.9 fold increase in \({\text{AUC}}_{{\text{0 - }}\infty } \)) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8–20%), in spite of good absorption (72–75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system.

Conclusions

The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first examples of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

Abbreviations

CM:

Chylomicron

CRA:

Cannabinoid receptor agonist

HDL:

High density lipoprotein

LDL:

Low density lipoprotein

TG:

Triglyceride

VLDL:

Very low density lipoprotein

References

  1. C. J. H. Porter, N. L. Trevaskis, and W. N. Charman. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat. Rev. Drug. Discov. 6:231–248 (2007). doi:10.1038/nrd2197.

    Article  PubMed  CAS  Google Scholar 

  2. C. M. O’Driscoll. Lipid-based formulations for intestinal lymphatic delivery. Eur. J. Pharm. Sci. 15:405–415 (2002). doi:10.1016/S0928-0987(02)00051-9.

    Article  PubMed  Google Scholar 

  3. D. M. Karpf, R. Holm, H. G. Kristensen, and A. Mullertz. Influence of the type of surfactant and the degree of dispersion on the lymphatic transport of halofantrine in conscious rats. Pharm. Res. 21:1413–1418 (2004). doi:10.1023/B:PHAM.0000036915.03725.19.

    Article  PubMed  CAS  Google Scholar 

  4. A. Dahan, R. Duvdevani, I. Shapiro, A. Elmann, E. Finkelstein, and A. Hoffman. The oral absorption of phospholipid prodrugs: in vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration. J. Control Release. 126:1–9 (2008). doi:10.1016/j.jconrel.2007.10.025.

    Article  PubMed  CAS  Google Scholar 

  5. A. Dahan, A. Mendelman, S. Amsili, N. Ezov, and A. Hoffman. The effect of general anesthesia on the intestinal lymphatic transport of lipophilic drugs: comparison between anesthetized and freely moving conscious rat models. Eur. J. Pharm. Sci. 32:367–374 (2007).

    PubMed  CAS  Google Scholar 

  6. P. Gershkovich, and A. Hoffman. Effect of a high-fat meal on absorption and disposition of lipophilic compounds: the importance of degree of association with triglyceride-rich lipoproteins. Eur. J. Pharm. Sci. 32:24–32 (2007). doi:10.1016/j.ejps.2007.05.109.

    Article  PubMed  CAS  Google Scholar 

  7. D. J. Hauss, S. C. Mehta, and G. W. Radebauch. Targeted lymphatic transport and modified systemic distribution of CI-976, a lipophilic lipid-regulator drug, via a formulation approach. Int. J. Pharm. 108:85–93 (1994). doi:10.1016/0378-5173(94)90318-2.

    Article  CAS  Google Scholar 

  8. N. L. Trevaskis, C. J. H. Porter, and W. N. Charman. An examination of the interplay between enterocyte-based metabolism and lymphatic drug transport in the rat. Drug Metab. Dispos. 34:729–733 (2006). doi:10.1124/dmd.105.008102.

    Article  PubMed  CAS  Google Scholar 

  9. D. M. Shackleford, W. A. Faassen, N. Houwing, H. Lass, G. A. Edwards, C. J. H. Porter, and W. N. Charman. Contribution of lymphatically transported testosterone undecanoate to the systemic exposure of testosterone after oral administration of two andriol formulations in conscious lymph duct-cannulated dogs. J. Pharmacol. Exp. Ther. 306:925–933 (2003). doi:10.1124/jpet.103.052522.

    Article  PubMed  CAS  Google Scholar 

  10. S. M. Khoo, G. A. Edwards, C. J. H. Porter, and W. N. Charman. A conscious dog model for assessing the absorption, enterocyte-based metabolism, and intestinal lymphatic transport of halofantrine. J. Pharm. Sci. 90:1599–1607 (2001). doi:10.1002/jps.1110.

    Article  PubMed  CAS  Google Scholar 

  11. S. M. Sieber, V. H. Cohn, and W. T. Wynn. The entry of foreign compounds into the thoracic duct lymph of the rat. Xenobiotica. 4:265–284 (1974).

    Article  PubMed  CAS  Google Scholar 

  12. A. Vost, and N. Maclean. Hydrocarbon transport in chylomicrons and high-density lipoproteins in rat. Lipids. 19:423–435 (1984). doi:10.1007/BF02537404.

    Article  PubMed  CAS  Google Scholar 

  13. C. T. Phan, and P. Tso. Intestinal lipid absorption and transport. Front Biosci. 6:D299–319 (2001). doi:10.2741/Phan.

    Article  PubMed  CAS  Google Scholar 

  14. B. K. Nordskog, C. T. Phan, D. F. Nutting, and P. Tso. An examination of the factors affecting intestinal lymphatic transport of dietary lipids. Adv. Drug. Deliv. Rev. 50:21–44 (2001). doi:10.1016/S0169-409X(01)00147-8.

    Article  PubMed  CAS  Google Scholar 

  15. C. J. H. Porter, and W. N. Charman. Intestinal lymphatic drug transport: an update. Adv. Drug Deliv. Rev. 50:61–80 (2001). doi:10.1016/S0169-409X(01)00151-X.

    Article  PubMed  CAS  Google Scholar 

  16. W. N. Charman, and V. J. Stella. Estimating the maximum potential for intestinal lymphatic transport of lipophilic drug molecules. Int. J. Pharm. 34:175–178 (1986). doi:10.1016/0378-5173(86)90027-X.

    Article  CAS  Google Scholar 

  17. C. A. Lipinski. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods. 44:235–249 (2000). doi:10.1016/S1056-8719(00)00107-6.

    Article  PubMed  CAS  Google Scholar 

  18. S. M. Khoo, D. M. Shackleford, C. J. H. Porter, G. A. Edwards, and W. N. Charman. Intestinal lymphatic transport of halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs. Pharm. Res. 20:1460–1465 (2003). doi:10.1023/A:1025718513246.

    Article  PubMed  CAS  Google Scholar 

  19. E. K. Dziadulewicz, S. J. Bevan, C. T. Brain, P. R. Coote, A. J. Culshaw, A. J. Davis, L. J. Edwards, A. J. Fisher, A. J. Fox, C. Gentry, A. Groarke, T. W. Hart, W. Huber, I. F. James, A. Kesingland, L. La Vecchia, Y. Loong, I. Lyothier, K. McNair, C. O’Farrell, M. Peacock, R. Portmann, U. Schopfer, M. Yaqoob, and J. Zadrobilek. Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration. J. Med. Chem. 50:3851–3856 (2007). doi:10.1021/jm070317a.

    Article  PubMed  CAS  Google Scholar 

  20. C. C. Felder, A. K. Dickason-Chesterfield, and S. A. Moore. Cannabinoids biology: the search for new therapeutic targets. Mol. Interv. 6:149–161 (2006). doi:10.1124/mi.6.3.6.

    Article  PubMed  CAS  Google Scholar 

  21. G. T. Whiteside, G. P. Lee, and K. J. Valenzano. The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists. Curr. Med. Chem. 14:917–936 (2007). doi:10.2174/092986707780363023.

    Article  PubMed  CAS  Google Scholar 

  22. A. Lespine, G. Chanoit, A. Bousquet-Melou, E. Lallemand, F. M. Bassissi, M. Alvinerie, and P. L. Toutain. Contribution of lymphatic transport to the systemic exposure of orally administered moxidectin in conscious lymph duct-cannulated dogs. Eur. J. Pharm. Sci. 27:37–43 (2006). doi:10.1016/j.ejps.2005.08.003.

    Article  PubMed  CAS  Google Scholar 

  23. G. A. Edwards, C. J. H. Porter, S. M. Caliph, S. M. Khoo, and W. N. Charman. Animal models for the study of intestinal lymphatic drug transport. Adv. Drug Deliv. Rev. 50:45–60 (2001). doi:10.1016/S0169-409X(01)00148-X.

    Article  PubMed  CAS  Google Scholar 

  24. T. T. Kararli. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug Dispos. 16:351–380 (1995). doi:10.1002/bdd.2510160502.

    Article  PubMed  CAS  Google Scholar 

  25. N. L. Trevaskis, C. J. H Porter, and W. N. Charman. Bile increases intestinal lymphatic drug transport in the fasted rat. Pharm. Res. 22:1863–1870 (2005). doi:10.1007/s11095-005-6808-9.

    Article  PubMed  CAS  Google Scholar 

  26. FDA, Center for Drug Evaluation and Research (CDER). Guidance for industry: food-effect bioavailability and fed bioequivalence studies. US, 2002.

Download references

Acknowledgments

Funding support from Novartis AG is gratefully acknowledged as well as the efforts of F Becher for bioanalytics, G Sedek for clinical pharmacology, E Nic Lochlainn for biostatistics, H Schiller, H Zehender, G Bruin, and M Zollinger for drug metabolism and pharmacokinetics.

Author information

Authors and Affiliations

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

    Natalie L. Trevaskis, William N. Charman & Christopher J. H. Porter

  2. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia

    David M. Shackleford

  3. Department of Veterinary Sciences, The University of Melbourne, Werribee, Victoria, Australia

    Glenn A. Edwards

  4. Novartis Pharma AG, Basel, Switzerland

    Anne Gardin, Silke Appel-Dingemanse, Olivier Kretz & Bruno Galli

Authors
  1. Natalie L. Trevaskis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David M. Shackleford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William N. Charman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Glenn A. Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Gardin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Silke Appel-Dingemanse
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Olivier Kretz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bruno Galli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christopher J. H. Porter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher J. H. Porter.

Additional information

Studies funded by Novartis Pharma AG.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trevaskis, N.L., Shackleford, D.M., Charman, W.N. et al. Intestinal Lymphatic Transport Enhances the Post-Prandial Oral Bioavailability of a Novel Cannabinoid Receptor Agonist Via Avoidance of First-Pass Metabolism. Pharm Res 26, 1486–1495 (2009). https://doi.org/10.1007/s11095-009-9860-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-009-9860-z

KEY WORDS

Search

Navigation