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  • Review Article
  • Published:

Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs

Nature Reviews Drug Discovery volume 6, pages 231–248 (2007)Cite this article

Key Points

  • Highly potent but poorly water-soluble drug (PWSD) candidates are common outcomes of contemporary drug discovery programmes. These lipophilic compounds often exhibit poor systemic exposure following oral administration.

  • Lipid-based formulations can significantly enhance the absorption of PWSDs following oral delivery. The three main mechanisms by which lipids and lipophilic excipients affect PWSD absorption are outlined below.

  • First, by enhancing drug solubilization in the intestinal milieu. Drug dissolution is a prerequisite for drug absorption from the small intestinal lumen into the intestinal absorptive cells (enterocytes), and the rate and extent of drug dissolution can be a limiting factor in the absorption of PWSDs. Lipid-based formulations enhance drug solubilization both by initially presenting the drug in a solubilized form and by preventing drug precipitation by altering the nature of both exogenous (formulation-derived) and endogenous solubilizing species in the intestinal milieu.

  • Second, by recruitment of intestinal lymphatic drug transport (and reduced first-pass metabolism). Highly lipophilic drugs (Log P > 5, triglyceride solubility >50 mg per g) can be transported to the systemic circulation by the intestinal lymphatic system rather than the portal vein blood following oral delivery. This transport is mediated by association of the lipophilic drug with lymphatic lipids. Lipid-based formulations (in particular, those that contain long-chain and unsaturated lipids) recruit endogenous and exogenous lipid transport and stimulate intestinal lymphatic transport of co-administered lipophilic drugs. By enhancing lymphatic transport, lipid-based formulations might protect PWSDs from first-pass metabolism.

  • Third, by altering enterocyte-based drug transport and disposition. Lipids and lipophilic excipients can interact with apical membrane lipid transporters, alter the expression of intracellular lipid-binding proteins and change the intracellular pooling of lipids within the enterocyte. In this way, lipid-based formulations can alter enterocyte lipid trafficking, which leads to an indirect effect on PWSD absorption and cellular disposition.

Abstract

Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development — most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.

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Figure 1: Potential effect of lipids and lipidic excipients on drug absorption.
Figure 2: Lipid digestion and drug solubilization in the small intestine.
Figure 3: Lipid digestion models for in vitro assessment of lipidic formulations.
Figure 4: Lipid and drug transport by the mesenteric lymph or portal blood following oral delivery.
Figure 5: Pathways of lipid absorption and pooling within the enterocyte.

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References

  1. Lipinski, C. A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 44, 235–249 (2000). A seminal paper in which it is made clear that modern approaches to drug discovery are leading to identification of drugs with higher lipophilicity and poor aqueous solubility and broadly discusses the relevance of solubility as a limitation to drug development.

    CAS  PubMed  Google Scholar 

  2. Persson, E. M. et al. A clinical single-pass perfusion investigation of the dynamic in vivo secretory response to a dietary meal in human proximal small intestine. Pharm. Res. 23, 742–751 (2006).

    CAS  PubMed  Google Scholar 

  3. Porter, C. J. H., Kaukonen, A. M., Boyd, B. J., Edwards, G. A. & Charman, W. N. Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation. Pharm.Res. 21, 1405–1412 (2004).

    CAS  PubMed  Google Scholar 

  4. Charman, W. N., Rogge, M. C., Boddy, A. W. & Berger, B. M. Effect of food and a monoglyceride emulsion formulation on danazol bioavailability. J. Clin. Pharmacol. 33, 381–386 (1993).

    CAS  PubMed  Google Scholar 

  5. Mueller, E. A. et al. Influence of a fat-rich meal on the pharmacokinetics of a new oral formulation of cyclosporine in a crossover comparison with the market formulation. Pharm. Res. 11, 151–155 (1994).

    CAS  PubMed  Google Scholar 

  6. Borovicka, J. et al. Regulation of gastric and pancreatic lipase secretion by CCK and cholinergic mechanisms in humans. Am. J. Physiol. 273, G374–G380 (1997).

    CAS  PubMed  Google Scholar 

  7. Moreau, H. et al. Immunocytolocalization of human gastric lipase in chief cells of the fundic mucosa. Histochemistry 91, 419–423 (1989).

    CAS  PubMed  Google Scholar 

  8. Thomson, A. B. R., Keelan, M., Garg, M. L. & Clandinin, M. T. Intestinal aspects of lipid absorption: in review. Can. J. Physiol. Pharmacol. 67, 179–191 (1989).

    CAS  PubMed  Google Scholar 

  9. Hamosh, M. et al. Fat digestion in the newborn. Characterization of lipase in gastric aspirates of premature and term infants. J. Clin. Invest. 67, 838–846 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Abrams, C. K. et al. Gastric lipase: localization in the human stomach. Gastroenterology 95, 1460–1464 (1988).

    CAS  PubMed  Google Scholar 

  11. Carriere, F., Barrowman, J. A., Verger, R. & Laugier, R. Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans. Gastroenterology 105, 876–888 (1993).

    CAS  PubMed  Google Scholar 

  12. Renou, C. et al. Effects of lansoprazole on human gastric lipase secretion and intragastric lipolysis in healthy human volunteers. Digestion 63, 207–213 (2001).

    CAS  PubMed  Google Scholar 

  13. Chapus, C., Semeriva, M., Bovier-Lapierre, C. & Desnuelle, P. Mechanism of pancreatic lipase action. 1. Interfacial activation of pancreatic lipase. Biochemistry 15, 4980–4987 (1976).

    CAS  PubMed  Google Scholar 

  14. Duane, W. C., Ginsberg, R. L. & Bennion, L. J. Effects of fasting on bile acid metabolism and biliary lipid composition in man. J. Lipid Res. 17, 211–219 (1976).

    CAS  PubMed  Google Scholar 

  15. Cunningham, K. M., Daly, J., Horowitz, M. & Read, N. W. Gastrointestinal adaptation to diets of differing fat composition in human volunteers. Gut 32, 483–486 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Feinle, C., Rades, T., Otto, B. & Fried, M. Fat digestion modulates gastrointestinal sensations induced by gastric distention and duodenal lipid in humans. Gastroenterology 120, 1100–1107 (2001).

    CAS  PubMed  Google Scholar 

  17. Fried, M. et al. Temporal relationships of cholecystokinin release, pancreatobiliary secretion, and gastric emptying of a mixed meal. Gastroenterology 95, 1344–1350 (1988).

    CAS  PubMed  Google Scholar 

  18. Feinle, C., Grundy, D. & Fried, M. Modulation of gastric distension-induced sensations by small intestinal receptors. Am. J. Physiol. 280, G51–G57 (2001).

    CAS  Google Scholar 

  19. Okumura, T., Fukagawa, K., Tso, P., Taylor, I. L. & Pappas, T. N. Apolioprotein A-IV acts in the brain to inhibit gastric emptying in the rat. Am. J. Physiol. 33, G49–G53 (1996).

    Google Scholar 

  20. Glatzle, J. et al. Chylomicron components mediate intestinal lipid-induced inhibition of gastric motor function. Am. J. Physiol. 282, G86–G91 (2002).

    CAS  Google Scholar 

  21. Tso, P. & Liu, M. Apolipoprotein A-IV, food intake, and obesity. Physiol. Behav. 83, 631–643 (2004).

    CAS  PubMed  Google Scholar 

  22. Raybould, H. E., Meyer, J. H., Tabrizi, Y., Liddle, R. A. & Tso, P. Inhibition of gastric emptying in response to intestinal lipid is dependent on chylomicron formation. Am. J. Physiol. 274, R1834–R1838 (1998).

    CAS  PubMed  Google Scholar 

  23. Ohtani, N., Sasaki, I., Naito, H., Shibata, C. & Matsuno, S. Mediators for fat-induced ileal brake are different between stomach and proximal small intestine in conscious dogs. J. Gastrointest. Surg. 5, 377–382 (2001).

    CAS  PubMed  Google Scholar 

  24. Van Citters, G. W. & Lin, H. C. The ileal brake: a fifteen-year progress report. Curr. Gastroenterol. Rep. 1, 404–409 (1999).

    CAS  PubMed  Google Scholar 

  25. Nordskog, B. K., Phan, C. T., Nutting, D. F. & Tso, P. An examination of the factors affecting intestinal lymphatic transport of dietary lipids. Adv. Drug Deliv. Rev. 50, 21–44 (2001).

    CAS  PubMed  Google Scholar 

  26. Thomson, A. B., Schoeller, C., Keelan, M., Smith, L. & Clandinin, M. T. Lipid absorption: passing through the unstirred layers, brush-border membrane, and beyond. Can. J. Physiol. Pharmacol. 71, 531–555 (1993).

    CAS  PubMed  Google Scholar 

  27. Porter, C. J. H. & Charman, W. N. In vitro assessment of oral lipid based formulations. Adv. Drug Deliv. Rev. 50, S127–S147 (2001).

    CAS  PubMed  Google Scholar 

  28. Persson, E. M. et al. The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids. Pharm. Res. 22, 2141–2151 (2005).

    CAS  PubMed  Google Scholar 

  29. Brouwers, J., Tack, J., Lammert, F. & Augustijns, P. Intraluminal drug and formulation behavior and integration in in vitro permeability estimation: a case study with amprenavir. J. Pharm. Sci. 95, 372–383 (2006).

    CAS  PubMed  Google Scholar 

  30. Kossena, G. A., Charman, W. N., Boyd, B. J., Dunstan, D. E. & Porter, C. J. H. Probing drug solubilisation patterns in the gastrointestinal tract after administration of lipid based delivery systems: a phase diagram approach. J. Pharm. Sci. 93, 332–348 (2004).

    CAS  PubMed  Google Scholar 

  31. Kossena, G. A., Boyd, B. J., Porter, C. J. & Charman, W. N. Separation and characterization of the colloidal phases produced on digestion of common formulation lipids and assessment of their impact on the apparent solubility of selected poorly water-soluble drugs. J. Pharm. Sci. 92, 634–648 (2003).

    CAS  PubMed  Google Scholar 

  32. Pedersen, B. L., Mullertz, A., Brondsted, H. & Kristensen, H. G. A comparison of the solubility of danazol in human and simulated gastrointestinal fluids. Pharm. Res. 17, 891–894 (2000).

    CAS  PubMed  Google Scholar 

  33. Kaukonen, A. M., Boyd, B. J., Porter, C. J. H. & Charman, W. N. Drug solubilization behaviour during in vitro digestion of simple triglyceride lipid solution formulations. Pharm. Res. 21, 245–253 (2004).

    CAS  PubMed  Google Scholar 

  34. Kossena, G. A., Charman, W. N., Boyd, B. J. & Porter, C. J. H. Influence of the intermediate digestion phases of common formulation lipids on the absorption of a poorly water-soluble drug. J. Pharm. Sci. 94, 481–492 (2005).

    CAS  PubMed  Google Scholar 

  35. Porter, C. J. H. et al. Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine. J. Pharm. Sci. 93, 1110–1121 (2004).

    CAS  PubMed  Google Scholar 

  36. Christensen, J. O., Schultz, K., Mollgaard, B., Kristensen, H. G. & Mullertz, A. Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium- and long-chain triacylglycerols. Eur. J. Pharm. Sci. 23, 287–296 (2004).

    CAS  PubMed  Google Scholar 

  37. Dahan, A. & Hoffman, A. Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs: correlation with in vivo data and the relationship to intra-enterocyte processes in rats. Pharm. Res. 23, 2165–2174 (2006).

    CAS  PubMed  Google Scholar 

  38. Reymond, J.-P., Sucker, H. & Vonderscher, J. In vivo model for ciclosporin intestinal absorption in lipid vehicles. Pharm. Res. 5, 677–679 (1988).

    CAS  PubMed  Google Scholar 

  39. Cuine, J. F., Charman, W. N., Pouton, C. W., Edwards, G. A. & Porter, C. J. H. Increasing the proportional content of surfactant (cremophor EL) relative to lipid in self-emulsifying lipid-based formulations of danazol reduces oral bioavailability in beagle dogs. Pharm. Res. 15 Feb 2007 (doi:10.1007/s11095-006-9194-z).

    PubMed  Google Scholar 

  40. Behrens, D. et al. Comparison of cyclosporin A absorption from LCT and MCT solutions following intrajejunal administration in conscious dogs. J. Pharm. Sci. 85, 666–668 (1996).

    CAS  PubMed  Google Scholar 

  41. Lucangioli, S. E. et al. Relation between retention factors of immunosuppressive drugs in microemulsion electrokinetic chromatography with biosurfactants and octanol–water partition coefficients. J. Pharm. Biomed. Anal. 33, 871–878 (2003).

    CAS  PubMed  Google Scholar 

  42. Myers, R. A. & Stella, V. J. Systemic bioavailability of penclomedine (NSC-338720) from oil-in-water emulsions administered intraduodenally to rats. Int. J. Pharm. 78, 217–226 (1992).

    CAS  Google Scholar 

  43. Caliph, S. M., Charman, W. N. & Porter, C. J. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J. Pharm. Sci. 89, 1073–1084 (2000).

    CAS  PubMed  Google Scholar 

  44. Pouton, C. W. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and 'self-microemulsifying' drug delivery systems. Eur. J. Pharm. Sci. 11, S93–S98 (2000).

    CAS  PubMed  Google Scholar 

  45. Gursoy, R. N. & Benita, S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipohilic drugs. Biomed. Pharmacother. 58, 173–182 (2004).

    PubMed  Google Scholar 

  46. Sek, L., Boyd, B. J., Charman, W. N. & Porter, C. J. Examination of the impact of a range of pluronic surfactants on the in-vitro solubilisation behaviour and oral bioavailability of lipidic formulations of atovaquone. J. Pharm. Pharmacol. 58, 809–820 (2006).

    CAS  PubMed  Google Scholar 

  47. Davidson, N. O. & Shelness, G. S. Apolipoprotein B: mRNA editing, lipoprotein assembly, and presecretory degradation. Annu. Rev. Nutr. 20, 169–193 (2000).

    CAS  PubMed  Google Scholar 

  48. Shelness, G. S. & Ledford, A. S. Evolution and mechanism of apolipoprotein B-containing lipoprotein assembly. Curr. Opin. Lipidol. 16, 325–332 (2005).

    CAS  PubMed  Google Scholar 

  49. Jong, M. C., Hofker, M. H. & Havekes, L. M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler. Thromb. Vasc. Biol. 19, 472–484 (1999).

    CAS  PubMed  Google Scholar 

  50. Shachter, N. S. Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism. Curr. Opin. Lipidol. 12, 297–304 (2001).

    CAS  PubMed  Google Scholar 

  51. van Dijk, K. W., Rensen, P. C., Voshol, P. J. & Havekes, L. M. The role and mode of action of apolipoproteins CIII and AV: synergistic actors in triglyceride metabolism? Curr. Opin. Lipidol. 15, 239–246 (2004).

    CAS  PubMed  Google Scholar 

  52. Mahley, R. W. & Rall, S. C. Jr. Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1, 507–537 (2000).

    CAS  PubMed  Google Scholar 

  53. Stojakovic, T., Scharnagl, H. & Marz, W. ApoE: crossroads between Alzheimer's disease and atherosclerosis. Semin. Vasc. Med. 4, 279–285 (2004).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  55. Vost, A. & Maclean, N. Hydrocarbon transport in chylomicrons and high-density lipoproteins in rat. Lipids 19, 423–435 (1984).

    CAS  PubMed  Google Scholar 

  56. Wasan, K. M., Ramaswamy, M., McIntosh, M. P., Porter, C. J. & Charman, W. N. Differences in the lipoprotein distribution of halofantrine are regulated by lipoprotein apolar lipid and protein concentration and lipid transfer protein I activity: in vitro studies in normolipidemic and dyslipidemic human plasmas. J. Pharm. Sci. 88, 185–190 (1999).

    CAS  PubMed  Google Scholar 

  57. Charman, W. N. & Stella, V. J. Estimating the maximum potential for intestinal lymphatic transport of lipophilic drug molecules. Int. J. Pharm. 34, 175–178 (1986). This article highlights the importance of log P and lipid solubility in indicating the potential for lymphatic drug transport and provides a working guideline for the identification of drugs, which might be lymphatically transported, based on physicochemical properties.

    CAS  Google Scholar 

  58. Lespine, A. et al. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  60. Porter, C. J., Charman, S. A., Humberstone, A. J. & Charman, W. N. Lymphatic transport of halofantrine in the conscious rat when administered as either the free base or the hydrochloride salt: effect of lipid class and lipid vehicle dispersion. J. Pharm. Sci. 85, 357–361 (1996).

    CAS  PubMed  Google Scholar 

  61. Ichihashi, T., Takagishi, Y. & Yamada, H. Factors determining the intrinsic lymphatic partition rate of epitiostanol and mepitiostane. Pharm. Res. 9, 1617–1621 (1992).

    CAS  PubMed  Google Scholar 

  62. Ichihashi, T., Kinoshita, H., Takagishi, Y. & Yamada, H. Effect of bile on absorption of mepitiostane by the lymphatic system in rats. J. Pharm. Pharmacol. 44, 565–569 (1992).

    CAS  PubMed  Google Scholar 

  63. Ichihashi, T., Kinoshita, H., Takagishi, Y. & Yamada, H. Effect of oily vehicles on absorption of mepitiostane by the lymphatic system in rats. J. Pharm. Pharmacol. 44, 560–564 (1992).

    CAS  PubMed  Google Scholar 

  64. Shackleford, D. M. et al. 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). This paper quantifies the contribution of lymphatic transport to the overall bioavailability of a drug in clinical usage and shows that lymphatic transport is the main contributing pathway for testosterone when administered orally in its clinical formulation.

    CAS  PubMed  Google Scholar 

  65. Kwei, G. Y. et al. Lymphatic uptake of MK-386, a sterol 5-α reductase inhibitor, from aqueous and lipid formulations. Int. J. Pharm. 164, 37–44 (1998).

    CAS  Google Scholar 

  66. Grimus, R. C. & Schuster, I. The role of the lymphatic transport in the enteral absorption of naftifine by the rat. Xenobiotica 14, 287–294 (1984).

    CAS  PubMed  Google Scholar 

  67. Palin, K. J. & Wilson, C. G. The effect of different oils on the absorption of probucol in the rat. J. Pharm. Pharmacol. 36, 641–643 (1984).

    CAS  PubMed  Google Scholar 

  68. Ueda, C. T., Lemaire, M., Gsell, G. & Nussbaumer, K. Intestinal lymphatic absorption of cyclosporin A following oral administration in an olive oil solution in rats. Biopharm. Drug Dispos. 4, 113–124 (1983).

    CAS  PubMed  Google Scholar 

  69. Hauss, D. J. et al. Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J. Pharm. Sci. 87, 164–169 (1998).

    CAS  PubMed  Google Scholar 

  70. Hauss, D. J., Mehta, S. & Radebaugh, G. W. 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).

    CAS  Google Scholar 

  71. Nankervis, R., Davis, S. S., Day, N. H. & Shaw, P. N. Intestinal lymphatic transport of three retinoids in the rat after oral administration: effect of lipophilicity and lipid vehicle. Int. J. Pharm. 130, 57–64 (1996).

    CAS  Google Scholar 

  72. Nishimukai, M. & Hara, H. Enteral administration of soybean phosphatidylcholine enhances the lymphatic absorption of lycopene, but reduces that of α-tocopherol in rats. J. Nutr. 134, 1862–1866 (2004).

    CAS  PubMed  Google Scholar 

  73. Trevaskis, N. L., Porter, C. J. & Charman, W. N. An examination of the interplay between enterocyte-based metabolism and lymphatic drug transport in the rat. Drug Metab. Dispos. 34, 729–733 (2006).

    CAS  PubMed  Google Scholar 

  74. Pantaleo, G. et al. Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol. Rev. 140, 105–130 (1994).

    CAS  PubMed  Google Scholar 

  75. Guadalupe, M. et al. Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection. J. Virol. 80, 8236–8247 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Edwards, G. A., Porter, C. J., Caliph, S. M., Khoo, S. M. & Charman, W. N. Animal models for the study of intestinal lymphatic drug transport. Adv. Drug Deliv. Rev. 50, 45–60 (2001).

    CAS  PubMed  Google Scholar 

  77. Boyd, M., Risovic, V., Jull, P., Choo, E. & Wasan, K. M. A stepwise surgical procedure to investigate the lymphatic transport of lipid-based oral drug formulations: cannulation of the mesenteric and thoracic lymph ducts within the rat. J. Pharmacol. Toxicol. Methods 49, 115–120 (2004).

    CAS  PubMed  Google Scholar 

  78. Hauss, D., Fogal, S. & Ficorilli, J. Chronic collection of mesenteric lymph from conscious, tethered rats. Contemp. Top. Lab. Anim. Sci. 37, 56–58 (1998).

    PubMed  Google Scholar 

  79. Girardet, R. E. & Benninghoff, D. L. Surgical techniques for long-term study of thoracic duct lymph circulation in dogs. J. Surg. Res. 15, 168–175 (1973).

    CAS  PubMed  Google Scholar 

  80. Girardet, R. E. Surgical techniques for long-term studies of thoracic duct circulation in the rat. J. Appl. Physiol. 39, 682–688 (1975).

    CAS  PubMed  Google Scholar 

  81. Dahan, A. & Hoffman, A. Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs. Eur. J. Pharm. Sci. 24, 381–388 (2005).

    CAS  PubMed  Google Scholar 

  82. Levy, E., Mehran, M. & Seidman, E. Caco-2 cells as a model for intestinal lipoprotein synthesis and secretion. FASEB J. 9, 626–635 (1995).

    CAS  PubMed  Google Scholar 

  83. Seeballuck, F., Ashford, M. B. & O'Driscoll, C. M. The effects of pluronics block copolymers and cremophor EL on intestinal lipoprotein processing and the potential link with P-glycoprotein in Caco-2 cells. Pharm. Res. 20, 1085–1092 (2003).

    CAS  PubMed  Google Scholar 

  84. Seeballuck, F., Lawless, E., Ashford, M. B. & O'Driscoll, C. M. Stimulation of triglyceride-rich lipoprotein secretion by polysorbate 80: in vitro and in vivo correlation using Caco-2 cells and a cannulated rat intestinal lymphatic model. Pharm. Res. 21, 2320–2326 (2004).

    CAS  PubMed  Google Scholar 

  85. Karpf, D. M. et al. Effect of different surfactants in biorelevant medium on the secretion of a lipophilic compound in lipoproteins using Caco-2 cell culture. J. Pharm. Sci. 95, 45–55 (2006).

    CAS  PubMed  Google Scholar 

  86. Khoo, S. M., Shackleford, D. M., Porter, C. J., Edwards, G. A. & Charman, W. N. 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).

    CAS  PubMed  Google Scholar 

  87. Porter, C. J. H. & Charman, W. N. Intestinal lymphatic transport: an update. Adv. Drug Deliv. Rev. 50, 61–80 (2001).

    CAS  PubMed  Google Scholar 

  88. O'Driscoll, C. M. Lipid-based formulations for intestinal lymphatic delivery. Eur. J. Pharm. Sci. 15, 405–415 (2002).

    CAS  PubMed  Google Scholar 

  89. Mansbach, C. M. II, Dowell, R. F. & Pritchett, D. Portal transport of absorbed lipids in rats. Am. J. Physiol. 261, G530–G538 (1991).

    CAS  PubMed  Google Scholar 

  90. McDonald, G. B. & Weidman, M. Partitioning of polar fatty acids into lymph and portal vein after intestinal absorption in the rat. Q. J. Exp. Physiol. 72, 153–159 (1987).

    CAS  PubMed  Google Scholar 

  91. Bloom, B., Chaikoff, I. L. & Reinhardt. Intestinal lymph as pathway for transport of absorbed fatty acids of different chain lengths. Am. J. Physiol. 166, 451–455 (1951).

    CAS  PubMed  Google Scholar 

  92. Chaikoff, I. L., Bloom, B., Stevens, B. P., Reinhardt, W. O. & Dauben, W. G. Pentadecanoic acid-5-C14; its absorption and lymphatic transport. J. Biol. Chem. 190, 431–435 (1951).

    CAS  PubMed  Google Scholar 

  93. Kiyasu, J. Y., Bloom, B. & Chaikoff, I. L. The portal transport of absorbed fatty acids. J. Biol. Chem. 199, 415–419 (1952).

    CAS  PubMed  Google Scholar 

  94. Ockner, R. K., Pittman, J. P. & Yager, J. L. Differences in the intestinal absorption of saturated and unsaturated long chain fatty acids. Gastroenterology 62, 981–992 (1972).

    CAS  PubMed  Google Scholar 

  95. Sheehe, D. M., Green, J. B. & Green, M. H. Influence of dietary fat saturation on lipid absorption in the rat. Atherosclerosis 37, 301–310 (1980).

    CAS  PubMed  Google Scholar 

  96. Feldman, E. B. et al. Dietary saturated fatty acid content affects lymph lipoproteins: studies in the rat. J. Lipid Res. 24, 967–976 (1983).

    CAS  PubMed  Google Scholar 

  97. Feldman, E. B., Russell, B. S., Hawkins, C. B. & Forte, T. Intestinal lymph lipoproteins in rats fed diets enriched in specific fatty acids. J. Nutr. 113, 2323–2334 (1983).

    CAS  PubMed  Google Scholar 

  98. Cheema, M., Palin, K. J. & Davis, S. S. Lipid vehicles for intestinal lymphatic drug absorption. J. Pharm. Pharmacol. 39, 55–56 (1987).

    CAS  PubMed  Google Scholar 

  99. Hayashi, H. et al. Fat feeding increases size, but not number, of chylomicrons produced by small intestine. Am. J. Physiol. 259, G709–G719 (1990).

    CAS  PubMed  Google Scholar 

  100. Bergstedt, S. E., Hayashi, H., Kritchevsky, D. & Tso, P. A comparison of absorption of glycerol tristearate and glycerol trioleate by rat small intestine. Am. J. Physiol. 259, G386–G393 (1990).

    CAS  PubMed  Google Scholar 

  101. Charman, W. N. & Stella, V. J. Effect of lipid class and lipid vehicle volume on the intestinal lymphatic transport of DDT. Int. J. Pharm. 33, 165–172 (1986).

    CAS  Google Scholar 

  102. Noguchi, T., Charman, W. N. & Stella, V. J. The effect of drug lipophilicity and lipid vehicles on the lymphatic absorption of various testosterone esters. Int. J. Pharm. 24, 173–184 (1985).

    CAS  Google Scholar 

  103. Trevaskis, N. L., Porter, C. J. & Charman, W. N. The lymph lipid precursor pool is a key determinant of intestinal lymphatic drug transport. J. Pharmacol. Exp. Ther. 316, 881–891 (2006). The first paper to specifically examine the effect of intracellular lipid pooling and processing on the enterocyte trafficking and intestinal lymphatic transport of a lipophilic drug.

    CAS  PubMed  Google Scholar 

  104. Koo, S. I. & Noh, S. K. Phosphatidylcholine inhibits and lysophosphatidylcholine enhances the lymphatic absorption of α-tocopherol in adult rats. J. Nutr. 131, 717–722 (2001).

    CAS  PubMed  Google Scholar 

  105. Porter, C. J., Charman, S. A. & Charman, W. N. Lymphatic transport of halofantrine in the triple-cannulated anesthetized rat model: effect of lipid vehicle dispersion. J. Pharm. Sci. 85, 351–356 (1996).

    CAS  PubMed  Google Scholar 

  106. Takada, K. et al. Enhanced lymphatic delivery of cyclosporin A by solubilisers and intensified immunosuppressive activity against mice skin allograft. Pharm. Res. 3, 48–51 (1986).

    CAS  PubMed  Google Scholar 

  107. Fukui, E. et al. Enhancing effect of medium-chain triglycerides on intestinal absorption of d-α-tocopherol acetate from lecithin-dispersed preparations in the rat. J. Pharmacobiodyn. 12, 80–86 (1989).

    CAS  PubMed  Google Scholar 

  108. Fernandez, E. & Borgstrom, B. Intestinal absorption of retinol and retinyl palmitate in the rat. Effects of tetrahydrolipstatin. Lipids 25, 549–552 (1990).

    CAS  PubMed  Google Scholar 

  109. Charman, W. N. & Porter, C. J. Lipophilic prodrugs designed for intestinal lymphatic transport. Adv. Drug Deliv. Rev. 19, 149–169 (1996).

    CAS  Google Scholar 

  110. Stella, V. J. & Pochopin, N. L. in Lymphatic transport of drugs (eds Charman, W. N. & Stella, V. J.) 181–210 (CRC press, Boca Raton, 1992).

    Google Scholar 

  111. Gershkovich, P. & Hoffman, A. Uptake of lipophilic drugs by plasma derived isolated chylomicrons: linear correlation with intestinal lymphatic bioavailability. Eur. J. Pharm. Sci. 26, 394–404 (2005).

    CAS  PubMed  Google Scholar 

  112. Velkov, T. et al. The interaction of lipophilic drugs with intestinal fatty acid-binding protein. J. Biol. Chem. 280, 17769–17776 (2005). One of the first publications to demonstrate the ability of intestinal fatty-acid-binding protein (FABP) to bind to drug molecules, and to suggest a potential role of FABP in facilitating intracellular drug trafficking and transport.

    CAS  PubMed  Google Scholar 

  113. Trevaskis, N. L., Porter, C. J. & Charman, W. N. Bile increases intestinal lymphatic drug transport in the fasted rat. Pharm. Res. 22, 1863–1870 (2005).

    CAS  PubMed  Google Scholar 

  114. Stremmel, W. Uptake of fatty acids by jejunal mucosal cells is mediated by a fatty acid binding membrane protein. J. Clin. Invest. 82, 2001–2010 (1988). The first article to identify a protein involved in carrier-mediated uptake of fatty acids across the apical membrane of enterocytes.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Chow, S. L. & Hollander, D. A dual, concentration-dependent absorption mechanism of linoleic acid by rat jejunum in vitro. J. Lipid Res. 20, 349–356 (1979).

    CAS  PubMed  Google Scholar 

  116. Strauss, E. W. Electron microscopic study of intestinal fat absorption in vitro from mixed micelles containing linolenic acid, monoolein, and bile salt. J. Lipid Res. 7, 307–723 (1966).

    CAS  PubMed  Google Scholar 

  117. Poirier, H., Degrace, P., Niot, I., Bernard, A. & Besnard, P. Localization and regulation of the putative membrane fatty-acid transporter (FAT) in the small intestine. Comparison with fatty acid-binding proteins (FABP). Eur. J. Biochem. 238, 368–373 (1996).

    CAS  PubMed  Google Scholar 

  118. Nauli, A. M. et al. CD36 is important for chylomicron formation and secretion and may mediate cholesterol uptake in the proximal intestine. Gastroenterology 131, 1197–1207 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Drover, V. A. et al. CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood. J. Clin. Invest. 115, 1290–1297 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Schoeller, C., Keelan, M., Mulvey, G., Stremmel, W. & Thomson, A. B. Role of a brush border membrane fatty acid binding protein in oleic acid uptake into rat and rabbit jejunal brush border membrane. Clin. Invest. Med. 18, 380–388 (1995).

    CAS  PubMed  Google Scholar 

  121. Stahl, A. et al. Identification of the major intestinal fatty acid transport protein. Mol. Cell 4, 299–308 (1999).

    CAS  PubMed  Google Scholar 

  122. Bietrix, F. et al. Accelerated lipid absorption in mice overexpressing intestinal SR-BI. J. Biol. Chem. 281, 7214–7219 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Lundgren, S. et al. Tissue distribution of human gp330/megalin, a putative Ca(2+)-sensing protein. J. Histochem. Cytochem. 45, 383–392 (1997).

    CAS  PubMed  Google Scholar 

  124. Murata, M. et al. VIP21/caveolin is a cholesterol-binding protein. Proc. Natl Acad. Sci. USA 92, 10339–10343 (1995).

    CAS  PubMed  Google Scholar 

  125. Ho, S. Y., Delgado, L. & Storch, J. Monoacylglycerol metabolism in human intestinal Caco-2 cells: evidence for metabolic compartmentation and hydrolysis. J. Biol. Chem. 277, 1816–1823 (2002).

    CAS  PubMed  Google Scholar 

  126. Ho, S. Y. & Storch, J. Common mechanisms of monoacylglycerol and fatty acid uptake by human intestinal Caco-2 cells. Am. J. Physiol. Cell. Physiol. 281, C1106–C1117 (2001).

    CAS  PubMed  Google Scholar 

  127. Murota, K. & Storch, J. Uptake of micellar long-chain fatty acid and sn-2-monoacylglycerol into human intestinal Caco-2 cells exhibits characteristics of protein-mediated transport. J. Nutr. 135, 1626–1630 (2005).

    CAS  PubMed  Google Scholar 

  128. Hauser, H. et al. Identification of a receptor mediating absorption of dietary cholesterol in the intestine. Biochemistry 37, 17843–17850 (1998).

    CAS  PubMed  Google Scholar 

  129. Davis, H. R. Jr. et al. Niemann–Pick C1Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. J. Biol. Chem. 279, 33586–33592 (2004).

    CAS  Google Scholar 

  130. Altmann, S. W. et al. Niemann–Pick C1Like 1 protein is critical for intestinal cholesterol absorption. Science 303, 1201–1204 (2004).

    CAS  Google Scholar 

  131. Brodin, B., Nielsen, C. U., Steffansen, B. & Frokjaer, S. Transport of peptidomimetic drugs by the intestinal Di/tri-peptide transporter, PepT1. Pharmacol. Toxicol. 90, 285–296 (2002).

    CAS  PubMed  Google Scholar 

  132. Mizuma, T., Ohta, K., Hayashi, M. & Awazu, S. Intestinal active absorption of sugar-conjugated compounds by glucose transport system: implication of improvement of poorly absorbable drugs. Biochem. Pharmacol. 43, 2037–2039 (1992).

    CAS  PubMed  Google Scholar 

  133. Kim, M. K. & Shim, C. K. The transport of organic cations in the small intestine: current knowledge and emerging concepts. Arch. Pharm. Res. 29, 605–616 (2006).

    CAS  PubMed  Google Scholar 

  134. Kim, R. B. Organic anion-transporting polypeptide (OATP) transporter family and drug disposition. Eur. J. Clin. Invest. 33 (Suppl. 2), 1–5 (2003).

    PubMed  Google Scholar 

  135. Balakrishnan, A. & Polli, J. E. Apical sodium dependent bile acid transporter (ASBT, SLC10A2): a potential prodrug target. Mol. Pharm. 3, 223–230 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Kunta, J. R. & Sinko, P. J. Intestinal drug transporters: in vivo function and clinical importance. Curr. Drug Metab. 5, 109–124 (2004).

    CAS  PubMed  Google Scholar 

  137. Oh, D. M., Han, H. K. & Amidon, G. L. Drug transport and targeting. Intestinal transport. Pharm. Biotechnol. 12, 59–88 (1999).

    CAS  PubMed  Google Scholar 

  138. Chan, L. M., Lowes, S. & Hirst, B. H. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur. J. Pharm. Sci. 21, 25–51 (2004).

    CAS  PubMed  Google Scholar 

  139. Sarkadi, B., Homolya, L., Szakacs, G. & Varadi, A. Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol. Rev. 86, 1179–1236 (2006).

    CAS  PubMed  Google Scholar 

  140. Wakabayashi, K., Tamura, A., Saito, H., Onishi, Y. & Ishikawa, T. Human ABC transporter ABCG2 in xenobiotic protection and redox biology. Drug Metab. Rev. 38, 371–391 (2006).

    CAS  PubMed  Google Scholar 

  141. Field, F. J. & Mathur, S. N. Intestinal lipoprotein synthesis and secretion. Prog. Lipid Res. 34, 185–198 (1995).

    CAS  PubMed  Google Scholar 

  142. Borst, P., Zelcer, N. & van Helvoort, A. ABC transporters in lipid transport. Biochim. Biophys. Acta 1486, 128–144 (2000).

    CAS  PubMed  Google Scholar 

  143. Smit, J. J. et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75, 451–462 (1993).

    CAS  PubMed  Google Scholar 

  144. Repa, J. J. et al. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289, 1524–1529 (2000).

    CAS  Google Scholar 

  145. Berge, K. E. et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290, 1771–1775 (2000).

    CAS  Google Scholar 

  146. Agellon, L. B., Toth, M. J. & Thomson, A. B. Intracellular lipid binding proteins of the small intestine. Mol. Cell. Biochem. 239, 79–82 (2002).

    CAS  PubMed  Google Scholar 

  147. Bass, N. M. The cellular fatty acid binding proteins: aspects of structure, regulation, and function. Int. Rev. Cytol. 111, 143–184 (1988).

    CAS  PubMed  Google Scholar 

  148. Besnard, P., Niot, I., Poirier, H., Clement, L. & Bernard, A. New insights into the fatty acid-binding protein (FABP) family in the small intestine. Mol. Cell. Biochem. 239, 139–147 (2002). An excellent general review of the proposed functions of fatty-acid binding protein (FABP) in the small intestine and changes to the expression of FABP along the length of the small intestine in response to lipids.

    CAS  PubMed  Google Scholar 

  149. Murphy, E. J. Sterol carrier protein-2: not just for cholesterol any more. Mol. Cell. Biochem. 239, 87–93 (2002).

    CAS  PubMed  Google Scholar 

  150. Seedorf, U., Ellinghaus, P. & Roch Nofer, J. Sterol carrier protein-2. Biochim. Biophys. Acta 1486, 45–54 (2000).

    CAS  PubMed  Google Scholar 

  151. Harrison, E. H. Mechanisms of digestion and absorption of dietary vitamin A. Annu. Rev. Nutr. 25, 87–103 (2005).

    CAS  PubMed  Google Scholar 

  152. Storch, J. & Thumser, A. E. The fatty acid transport function of fatty acid-binding proteins. Biochim. Biophys. Acta 1486, 28–44 (2000).

    CAS  PubMed  Google Scholar 

  153. Montoudis, A. et al. Intestinal-fatty acid binding protein and lipid transport in human intestinal epithelial cells. Biochem. Biophys. Res. Commun. 339, 248–254 (2006).

    CAS  PubMed  Google Scholar 

  154. Trevaskis, N. L. et al. An acute and coincident increase in FABP expression and lymphatic lipid and drug transport occurs during intestinal infusion of lipid-based drug formulations to rats. Pharm. Res. 23, 1786–1796 (2006).

    CAS  PubMed  Google Scholar 

  155. Constantinides, P. P. & Wasan, K. M. Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: in vitro/in vivo case studies. J. Pharm. Sci. 96, 235–248 (2007).

    CAS  PubMed  Google Scholar 

  156. Wasan, K. M. Role of Lipid Excipients in Modifying Oral And Parenteral Drug Delivery: Basic Principles And Biological Examples (ed. Wasan, K. M.) (John Wiley & Sons Inc, Hoboken, 2006).

    Google Scholar 

  157. Rege, B. D., Kao, J. P. & Polli, J. E. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur. J. Pharm. Sci. 16, 237–246 (2002).

    CAS  PubMed  Google Scholar 

  158. Cornaire, G. et al. Effect of polyoxyl 35 castor oil and polysorbate 80 on the intestinal absorption of digoxin in vitro. Arzneimittelforschung 50, 576–579 (2000).

    CAS  PubMed  Google Scholar 

  159. Chiu, Y. Y. et al. Human jejunal permeability of cyclosporin A: influence of surfactants on P-glycoprotein efflux in Caco-2 cells. Pharm. Res. 20, 749–756 (2003).

    CAS  PubMed  Google Scholar 

  160. Johnson, B. M., Charman, W. N. & Porter, C. J. An in vitro examination of the impact of polyethylene glycol 400, pluronic P85, and vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine. AAPS PharmSci 4, e40 (2002).

    PubMed  Google Scholar 

  161. Bogman, K., Erne-Brand, F., Alsenz, J. & Drewe, J. The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins. J. Pharm. Sci. 92, 1250–1261 (2003).

    CAS  PubMed  Google Scholar 

  162. Batrakova, E. V., Li, S., Miller, D. W. & Kabanov, A. V. Pluronic P85 increases permeability of a broad spectrum of drugs in polarized BBMEC and Caco-2 cell monolayers. Pharm. Res. 16, 1366–1372 (1999).

    CAS  PubMed  Google Scholar 

  163. Hugger, E. D., Novak, B. L., Burton, P. S., Audus, K. L. & Borchardt, R. T. A comparison of commonly used polyethoxylated pharmaceutical excipients on their ability to inhibit P-glycoprotein activity in vitro. J. Pharm. Sci. 91, 1991–2002 (2002).

    CAS  PubMed  Google Scholar 

  164. Lo, Y. L. Relationships between the hydrophilic–lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in Caco-2 cells and rat intestines. J. Control. Release 90, 37–48 (2003).

    CAS  PubMed  Google Scholar 

  165. Zastre, J. et al. Enhanced cellular accumulation of a P-glycoprotein substrate, rhodamine-123, by Caco-2 cells using low molecular weight methoxypolyethylene glycol-block-polycaprolactone diblock copolymers. Eur. J. Pharm. Biopharm. 54, 299–309 (2002).

    CAS  PubMed  Google Scholar 

  166. Katneni, K., Charman, S. A. & Porter, C. J. The impact of cremophor-EL and polysorbate-80 on digoxin permeability across rat jejunum: delineation of thermodynamic and transporter related events using the reciprocal permeability approach. J. Pharm. Sci. 96, 280–293 (2006).

    Google Scholar 

  167. Wandel, C., Kim, R. B. & Stein, C. M. 'Inactive' excipients such as cremophor can affect in vivo drug disposition. Clin. Pharmacol. Ther. 73, 394–396 (2003).

    CAS  PubMed  Google Scholar 

  168. Collnot, E. M. et al. Influence of vitamin E TPGS poly(ethylene glycol) chain length on apical efflux transporters in Caco-2 cell monolayers. J. Control. Release 111, 35–40 (2006).

    CAS  PubMed  Google Scholar 

  169. Shono, Y. et al. Modulation of intestinal P-glycoprotein function by cremophor EL and other surfactants by an in vitro diffusion chamber method using the isolated rat intestinal membranes. J. Pharm. Sci. 93, 877–885 (2004).

    CAS  PubMed  Google Scholar 

  170. Cornaire, G. et al. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int. J. Pharm. 278, 119–131 (2004).

    CAS  PubMed  Google Scholar 

  171. Bogman, K. et al. P-glycoprotein and surfactants: effect on intestinal talinolol absorption. Clin. Pharmacol. Ther. 77, 24–32 (2005). One of the first well-controlled studies that demonstrates both in vitro and in vivo evidence of the ability of a lipidic excipient to inhibit P-glycoprotein-mediated drug efflux.

    CAS  PubMed  Google Scholar 

  172. Katneni, K., Charman, S. A. & Porter, C. J. Permeability assessment of poorly water-soluble compounds under solubilizing conditions: the reciprocal permeability approach. J. Pharm. Sci. 95, 2170–2185 (2006).

    CAS  PubMed  Google Scholar 

  173. Wu, C. Y. & Benet, L. Z. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm. Res. 22, 11–23 (2005).

    CAS  PubMed  Google Scholar 

  174. Konishi, T. et al. A bitter melon extract inhibits the P-glycoprotein activity in intestinal Caco-2 cells: monoglyceride as an active compound. Biofactors 22, 71–74 (2004).

    CAS  PubMed  Google Scholar 

  175. Konishi, T. et al. Inhibitory effect of a bitter melon extract on the P-glycoprotein activity in intestinal Caco-2 cells. Br. J. Pharmacol. 143, 379–387 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Ingels, F., Beck, B., Oth, M. & Augustijns, P. Effect of simulated intestinal fluid on drug permeability estimation across Caco-2 monolayers. Int. J. Pharm. 274, 221–232 (2004).

    CAS  PubMed  Google Scholar 

  177. Sukhotnik, I. et al. Effect of bowel resection and high-fat diet on heart CD36/fatty-acid translocase expression in a rat model of short-bowel syndrome. Pediatr. Surg. Int. 18, 620–623 (2002).

    PubMed  Google Scholar 

  178. Motojima, K., Passilly, P., Peters, J. M., Gonzalez, F. J. & Latruffe, N. Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor α and γ activators in a tissue- and inducer-specific manner. J. Biol. Chem. 273, 16710–16714 (1998).

    CAS  PubMed  Google Scholar 

  179. Niot, I., Poirier, H. & Besnard, P. Regulation of gene expression by fatty acids: special reference to fatty acid-binding protein (FABP). Biochimie 79, 129–133 (1997).

    CAS  PubMed  Google Scholar 

  180. Willson, T. M. & Kliewer, S. A. PXR, CAR and drug metabolism. Nature Rev. Drug Discov. 1, 259–266 (2002).

    CAS  Google Scholar 

  181. Meunier-Durmort, C., Poirier, H., Niot, I., Forest, C. & Besnard, P. Up-regulation of the expression of the gene for liver fatty acid-binding protein by long-chain fatty acids. Biochem. J. 319, 483–487 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Ockner, R. K., Manning, J. A., Poppenhausen, R. B. & Ho, W. K. A binding protein for fatty acids in cytosol of intestinal mucosa, liver, myocardium, and other tissues. Science 177, 56–58 (1972).

    CAS  PubMed  Google Scholar 

  183. Poirier, H. et al. Fatty acid regulation of fatty acid-binding protein expression in the small intestine. Am. J. Physiol. 273, G289–G295 (1997).

    CAS  PubMed  Google Scholar 

  184. Poirier, H. et al. Differential involvement of peroxisome-proliferator-activated receptors α and δ in fibrate and fatty-acid-mediated inductions of the gene encoding liver fatty-acid-binding protein in the liver and the small intestine. Biochem. J. 355, 481–488 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Dube, N. et al. Modulation of intestinal and liver fatty acid-binding proteins in Caco-2 cells by lipids, hormones and cytokines. J. Cell. Biochem. 81, 613–620 (2001).

    CAS  PubMed  Google Scholar 

  186. Mansbach, C. M. 2nd & Dowell, R. F. Role of the intestine in chylomicron remnant clearance. Am. J. Physiol. 269, G144–G152 (1995).

    CAS  PubMed  Google Scholar 

  187. Shiau, Y. F. et al. Intestinal triglycerides are derived from both endogenous and exogenous sources. Am. J. Physiol. 248, G164–G169 (1985).

    CAS  PubMed  Google Scholar 

  188. Mansbach, C. M. 2nd & Dowell, R. F. Uptake and metabolism of circulating fatty acids by rat intestine. Am. J. Physiol. 263, G927–G933 (1992).

    CAS  PubMed  Google Scholar 

  189. Mansbach, C. M. 2nd, Arnold, A. & Cox, M. A. Factors influencing triacylglycerol delivery into mesenteric lymph. Am. J. Physiol. 249, G642–G648 (1985).

    CAS  PubMed  Google Scholar 

  190. Tso, P. & Balint, J. A. Formation and transport of chylomicrons by enterocytes to the lymphatics. Am. J. Physiol. 250, G715–G726 (1986).

    CAS  PubMed  Google Scholar 

  191. Tso, P., Balint, J. A. & Simmonds, W. J. Role of biliary lecithin in lymphatic transport of fat. Gastroenterology 73, 1362–1367 (1977).

    CAS  PubMed  Google Scholar 

  192. Bell, R. M., Ballas, L. M. & Coleman, R. A. Lipid topogenesis. J. Lipid Res. 22, 391–403 (1981).

    CAS  PubMed  Google Scholar 

  193. Johnston, J. M. & Rao, G. A. Triglyceride biosynthesis in the intestinal mucosa. Biochim. Biophys. Acta 106, 1–9 (1965).

    CAS  PubMed  Google Scholar 

  194. Rao, G. A. & Johnston, J. M. Purification and properties of triglyceride synthetase from the intestinal mucosa. Biochim. Biophys. Acta 125, 465–473 (1966).

    CAS  PubMed  Google Scholar 

  195. Lehner, R. & Kuksis, A. Biosynthesis of triacylglycerols. Prog. Lipid Res. 35, 169–201 (1996).

    CAS  PubMed  Google Scholar 

  196. Hussain, M. M., Iqbal, J., Anwar, K., Rava, P. & Dai, K. Microsomal triglyceride transfer protein: a multifunctional protein. Front. Biosci. 8, S500–S506 (2003).

    CAS  PubMed  Google Scholar 

  197. Hussain, M. M., Shi, J. & Dreizen, P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J. Lipid Res. 44, 22–32 (2003).

    CAS  PubMed  Google Scholar 

  198. Yang, L. Y. & Kuksis, A. Apparent convergence (at 2-monoacylglycerol level) of phosphatidic acid and 2-monoacylglycerol pathways of synthesis of chylomicron triacylglycerols. J. Lipid Res. 32, 1173–1186 (1991).

    CAS  PubMed  Google Scholar 

  199. Tipton, A. D. t., Frase, S. & Mansbach, C. M. 2nd. Isolation and characterization of a mucosal triacylglycerol pool undergoing hydrolysis. Am. J. Physiol. 257, G871–G878 (1989).

    CAS  PubMed  Google Scholar 

  200. Mahan, J. T., Heda, G. D., Rao, R. H. & Mansbach, C. M. 2nd. The intestine expresses pancreatic triacylglycerol lipase: regulation by dietary lipid. Am. J. Physiol. 280, G1187–G1196 (2001).

    CAS  Google Scholar 

  201. Nevin, P., Koelsch, D. & Mansbach, C. M. 2nd. Intestinal triacylglycerol storage pool size changes under differing physiological conditions. J. Lipid. Res. 36, 2405–2412 (1995).

    CAS  PubMed  Google Scholar 

  202. Mansbach, C. M. 2nd & Arnold, A. Steady-state kinetic analysis of triacylglycerol delivery into mesenteric lymph. Am. J. Physiol. 251, G263–G269 (1986).

    CAS  PubMed  Google Scholar 

  203. Erlanson-Albertsson, C. Pancreatic colipase. Structural and physiological aspects. Biochim. Biophys. Acta 1125, 1–7 (1992).

    CAS  PubMed  Google Scholar 

  204. Borgstrom, B. On the mechanism of pancreatic lipolysis of glycerides. Biochim. Biophys. Acta 13, 491–504 (1954).

    CAS  PubMed  Google Scholar 

  205. van den Bosch, H., Postema, N. M., de Haas, G. H. & van Deenen, L. L. On the positional specificity of phospholipase A from pancreas. Biochim. Biophys. Acta 98, 657–659 (1965).

    CAS  PubMed  Google Scholar 

  206. Borgstrom, B., Dahlqvist, A., Lundh, G. & Sjovall, J. Studies of intestinal digestion and absorption in the human. J. Clin. Invest. 36, 1521–1536 (1957).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Phan, C. T. & Tso, P. Intestinal lipid absorption and transport. Front. Biosci. 6, d299–d319 (2001).

    CAS  PubMed  Google Scholar 

  208. Kalantzi, L. et al. Canine intestinal contents vs. simulated media for the assessment of solubility of two weak bases in the human small intestinal contents. Pharm. Res. 23, 1373–1381 (2006).

    CAS  PubMed  Google Scholar 

  209. Pedersen, B. L. et al. Dissolution of hydrocortisone in human and simulated intestinal fluids. Pharm. Res. 17, 183–189 (2000).

    CAS  PubMed  Google Scholar 

  210. Armand, M. et al. Physicochemical characteristics of emulsions during fat digestion in human stomach and duodenum. Am. J. Physiol. 271, G172–G183 (1996).

    CAS  PubMed  Google Scholar 

  211. Lindahl, A., Ungell, A., Knutson, L. & Lennernas, H. Characterisation of fluids from the stomach and proximal jejunum in men and women. Pharm. Res. 14, 497–502 (1997).

    CAS  PubMed  Google Scholar 

  212. Hernell, O., Staggers, J. E. & Carey, M. C. Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 2. Phase analysis and aggregation states of luminal lipids during duodenal fat digestion in healthy adult human beings. Biochemistry 29, 2041–2056 (1990).

    CAS  PubMed  Google Scholar 

  213. Tangerman, A., van Schaik, A. & van der Hock, E. W. Analysis of conjugated and unconjugated bile acids in serum and jejunal fluid of normal subjects. Clin. Chim. Acta 159, 123–132 (1986).

    CAS  PubMed  Google Scholar 

  214. Ladas, S. D., Isaacs, P. E. T., Murphy, G. M. & Sladen, G. E. Comparison of the effects of medium and long chain triglyceride containing liquid meals on gall bladder and small intestinal function in normal man. Gut 25, 405–411 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Peeters, T. L., Vantrappen, G. & Janssens, J. Bile acid output and the interdigestive migrating motor complex in normals and in cholecystectomy patients. Gastroenterology 79, 678–681 (1980).

    CAS  PubMed  Google Scholar 

  216. Rautureau, M., Bisalli, A. & Rambaud, J. C. Bile salts and lipids in aqueous intraluminal phase during the digestion of a standard meal in normal man. Gastroenterol. Clin. Biol. 5, 417–425 (1981).

    CAS  PubMed  Google Scholar 

  217. Fausa, O. Duodenal bile acids after a test meal. Scand. J. Gastroenterol. 9, 567–570 (1974).

    CAS  PubMed  Google Scholar 

  218. Westergaard, H. & Dietschy, J. M. The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell. J. Clin. Invest. 58, 97–108 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Dulfer, W. J., Groten, J. P. & Govers, H. A. Effect of fatty acids and the aqueous diffusion barrier on the uptake and transport of polychlorinated biphenyls in Caco-2 cells. J. Lipid Res. 37, 950–961 (1996).

    CAS  PubMed  Google Scholar 

  220. Simmonds, W. J. The role of micellar solubilisation in lipid absorption. Aust. J. Exp. Biol. Med. Sci. 50, 403–421 (1972).

    CAS  PubMed  Google Scholar 

  221. Hoffman, N. E. The relationship between uptake in vitro of oleic acid and micellar solubilization. Biochim. Biophys. Acta 196, 193–203 (1970).

    CAS  PubMed  Google Scholar 

  222. Ring, A., Pohl, J., Volkl, A. & Stremmel, W. Evidence for vesicles that mediate long-chain fatty acid uptake by human microvascular endothelial cells. J. Lipid Res. 43, 2095–2104 (2002).

    CAS  PubMed  Google Scholar 

  223. Pohl, J., Ring, A. & Stremmel, W. Uptake of long-chain fatty acids in HepG2 cells involves caveolae: analysis of a novel pathway. J. Lipid Res. 43, 1390–1399 (2002).

    CAS  PubMed  Google Scholar 

  224. Pohl, J. et al. Long-chain fatty acid uptake into adipocytes depends on lipid raft function. Biochemistry 43, 4179–4187 (2004).

    CAS  PubMed  Google Scholar 

  225. Lucas, M. L., Schneider, W., Haberich, F. J. & Blair, J. A. Direct measurement by pH-micorelectrode of the pH microclimate in rat proximal jejunum. Proc. R. Soc. Lond., B, Biol. Sci. 192, 39–48 (1975).

    CAS  PubMed  Google Scholar 

  226. Shiau, Y., Kelemen, R. J. & Reed, M. A. Acidic mucin layer facilitates micelle dissociation and fatty acid diffusion. Am. J. Physiol. 259, G671–G675 (1990).

    CAS  PubMed  Google Scholar 

  227. Patton, J. S. & Carey, M. C. Watching fat digestion. Science 204, 145–148 (1979). This is one of the first studies to visualize and describe the phase changes that occur during the digestion of dietary lipids in the small intestine.

    CAS  PubMed  Google Scholar 

  228. Staggers, J. E., Hernell, O., Stafford, R. J. & Carey, M. C. Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 1. Phase behavior and aggregation states of model lipid systems patterned after aqueous duodenal contents of healthy adult human beings. Biochemistry 29, 2028–2040 (1990). This study is one of two in a series that uses a phase diagram approach to describe the physicochemical changes to lipidic species in the gastrointestinal tract during the digestion of lipids.

    CAS  PubMed  Google Scholar 

  229. Chawla, A., Repa, J. J., Evans, R. M. & Mangelsdorf, D. J. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870 (2001).

    CAS  PubMed  Google Scholar 

  230. Xie, W. & Evans, R. M. Orphan nuclear receptors: the exotics of xenobiotics. J. Biol. Chem. 276, 37739–37742 (2001).

    CAS  PubMed  Google Scholar 

  231. Blumberg, B. & Evans, R. M. Orphan nuclear receptors — new ligands and new possibilities. Genes Dev. 12, 3149–3155 (1998).

    CAS  PubMed  Google Scholar 

  232. Kliewer, S. A., Xu, H. E., Lambert, M. H. & Willson, T. M. Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog. Horm. Res. 56, 239–263 (2001).

    CAS  PubMed  Google Scholar 

  233. Peet, D. J., Janowski, B. A. & Mangelsdorf, D. J. The LXRs: a new class of oxysterol receptors. Curr. Opin. Genet. Dev. 8, 571–575 (1998).

    CAS  PubMed  Google Scholar 

  234. Kalaany, N. Y. & Mangelsdorf, D. J. LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu. Rev. Physiol. 68, 159–191 (2006).

    CAS  PubMed  Google Scholar 

  235. Francis, G. A., Fayard, E., Picard, F. & Auwerx, J. Nuclear receptors and the control of metabolism. Annu. Rev. Physiol. 65, 261–311 (2003).

    CAS  PubMed  Google Scholar 

  236. Kretschmer, X. C. & Baldwin, W. S. CAR and PXR: xenosensors of endocrine disrupters? Chem. Biol. Interact. 155, 111–128 (2005).

    CAS  PubMed  Google Scholar 

  237. Oliver, W. R. Jr. et al. A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. Proc. Natl Acad. Sci. USA 98, 5306–5311 (2001).

    CAS  PubMed  Google Scholar 

  238. Vosper, H. et al. The peroxisome proliferator-activated receptor δ promotes lipid accumulation in human macrophages. J. Biol. Chem. 276, 44258–44265 (2001).

    CAS  PubMed  Google Scholar 

  239. Peters, J. M. et al. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor β(δ). Mol. Cell. Biol. 20, 5119–5128 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Tso, P., Drake, D. S., Black, D. D. & Sabesin, S. M. Evidence for separate pathways of chylomicron and very low-density lipoprotein assembly and transport by rat small intestine. Am. J. Physiol. 247, G599–G610 (1984).

    CAS  PubMed  Google Scholar 

  241. Hussain, M. M. A proposed model for the assembly of chylomicrons. Atherosclerosis 148, 1–15 (2000).

    CAS  PubMed  Google Scholar 

  242. Valyi-Nagy, K., Harris, C. & Swift, L. L. The assembly of hepatic very low density lipoproteins: evidence of a role for the Golgi apparatus. Lipids 37, 879–884 (2002).

    CAS  PubMed  Google Scholar 

  243. Reymond, J. P. & Sucker, H. In vitro model for ciclosporin intestinal absorption in lipid vehicles. Pharm. Res. 5, 673–676 (1988). This article provides the first description of the use of an in vitro lipid digestion model to model the patterns of solubilization of a lipophilic drug in the intestinal milieu.

    CAS  PubMed  Google Scholar 

  244. White, D. G., Story, M. J. & Barnwell, S. G. An experimental animal model for studying the effects of a novel lymphatic drug delivery system for propranolol. Int. J. Pharm. 69, 169–174 (1991).

    CAS  Google Scholar 

  245. Ehehalt, R. et al. Translocation of long chain fatty acids across the plasma membrane — lipid rafts and fatty acid transport proteins. Mol. Cell. Biochem. 284, 135–140 (2006). An excellent review outlining the potential mechanisms by which fatty acids can cross plasma membranes throughout the body.

    CAS  PubMed  Google Scholar 

  246. Hussain, M. M., Fatma, S., Pan, X. & Iqbal, J. Intestinal lipoprotein assembly. Curr. Opin. Lipidol. 16, 281–285 (2005). An excellent review of the process of lipoprotein assembly in the small intestine.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Parkville campus, 381 Royal Parade, Parkville, 3052, Victoria, Australia

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

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  1. Christopher J. H. Porter
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Department of Pharmaceutics, Monash University

Glossary

Enterocyte

The absorptive cells lining the small intestine.

Dissolution rate

The rate at which a solute (for example, a drug) dissolves in a solvent.

Polymorphs

A specific crystalline form of a compound (for example, a drug) that exhibits polymorphism, that is the ability to crystallize in different forms.

Solid dispersion

A solid-dose formulation that comprises a molecular mixture of a drug and a highly water-soluble excipient (commonly polyethylene glycol or polyvinylpyrrolidone).

Post-prandial

After a meal.

Post-prandial response

The physiological response that occurs after ingestion of a meal (in particular, a fatty meal) including delayed gastric emptying, release of bile and pancreatic secretions, and alterations in gastrointestinal motility and secretions.

Bile

A fluid secreted from hepatocytes in the liver and stored in the gall bladder before release into the small intestine. The primary constituents of bile are water, bile salt, cholesterol, phospholipid, bicarbonate, bile pigments and organic wastes. Bile salt, cholesterol and phospholipid are co-secreted in bile in the form of mixed micellar complexes in a molar ratio of approximately 16:4:1.

Critical micelle concentration

The minimum concentration of a surfactant in a bulk solution that leads to spontaneous formation of surfactant micelles. Also, the concentration of free surfactant in solution that is in equilibrium with surfactants in a micellar (aggregated) form.

First-pass metabolism

Drugs administered orally are typically taken up into the enterocytes lining the upper small intestine and transported by the mesenteric vessels to the hepatic portal vein and then to the liver before reaching the systemic circulation. First-pass metabolism refers to the metabolism of a drug within the liver and enterocytes before the drug first reaches the systemic circulation.

Lipoproteins

Colloidal particles synthesized in the liver and small intestine that consist of a hydrophobic core (containing triglyceride and cholesteryl esters) and a hydrophilic surface (containing phospholipids, cholesterol and apolipoproteins). Lipoproteins facilitate the transport of lipids and lipophilic substances around the body.

Chylomicrons

Chylomicrons are larger (50–500 nM) and less dense (Sf > 400) lipoproteins than very low-density lipoproteins, and are formed exclusively in the small intestine following the ingestion of lipids (dietary-derived or formulation-derived).

VLDL

Very low-density lipoproteins (VLDL) are small (20–50 nM) and more dense (Sf = 20–400) lipoproteins than chylomicrons, and are formed in the liver and the small intestine (where they are the predominant lipoproteins secreted in the fasted state).

Log D7.4

Log10 of the octanol–water partition co-efficient of a molecule (for example, a drug) at pH 7.4.

Pluronic L-81

A hydrophobic surfactant that blocks intestinal chylomicron secretion at the pre-Golgi level without affecting triacylglycerol uptake into the enterocytes, or triglyceride re-esterification in the smooth endoplasmic reticulum.

Colchicine

Clinically used to treat gout and has also been shown to cause accumulation of lipoproteins in the smooth endoplasmic reticulum and Golgi, thereby blocking chylomicron exit from the enterocytes.

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

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