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Low Dose Lipid Formulations: Effects on Gastric Emptying and Biliary Secretion

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Abstract

Purpose

Food stimulates changes to gastrointestinal secretion and motility patterns, however, the effect of smaller quantities of lipid, such as that contained in a lipid-based drug formulation, has not been detailed. This study aimed to examine the effects of small quantities of lipid on gastric emptying and biliary secretion.

Methods

The influence of oral administration of three lipid-based formulations and a negative control formulation on gastric emptying and biliary secretion was evaluated in 16 healthy male subjects using gamma scintigraphy, ultrasonography and duodenal aspiration.

Results

Low quantities (2 g) of long chain lipid stimulated gall bladder contraction and elevated intestinal bile salt, phospholipid and cholesterol levels. Changes in gastric emptying were also evident, although these did not reach statistical significance. Administration of a similar quantity of medium chain lipid, however, had little effect on gastric emptying and gallbladder contraction and did not stimulate appreciable increases in intestinal concentrations of biliary-derived lipids.

Conclusions

The quantities of long chain lipid that might be administered in a pharmaceutical formulation stimulate gallbladder contraction and elevate intestinal levels of bile salt and phospholipid. This effect is a likely contributor to the ability of lipid based formulations to enhance the absorption of poorly water-soluble drugs.

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References

  1. P. Borel, B. Pasquier, M. Armand, V. Tyssandier, P. Grolier, M. Alexandre-Gouabau, M. Andre, M. Senft, J. Peyrot, V. Jaussan, D. Lairon, and V. Azais-Braesco. Processing of vitamin A and E in the human gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 280:G95–G103 (2001).

    PubMed  CAS  Google Scholar 

  2. N. Aoyagi, H. Ogata, N. Kaniwa, and A. Ejima. Effect of food on the bioavailability of griseofulvin from microsize and PEG ultramicrosize (GRIS-PEG) plain tablets. J. Pharmacobio-Dyn. 5:120–124 (1982).

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  4. A. J. Humberstone, C. J. H. Porter, and W. N. Charman. A physicochemical basis for the effect of food on the absolute oral bioavailability of halofantrine. J. Pharm. Sci. 85:525–529 (1996).

    Article  PubMed  CAS  Google Scholar 

  5. E. Nicolaides, M. Symillides, J. B. Dressman, and C. Reppas. Biorelevant dissolution testing to predict the plasma profile of lipophilic drugs after oral administration. Pharm. Res. 18:380–388 (2001).

    Article  PubMed  CAS  Google Scholar 

  6. L. E. Schmidt and K. Dalhoff. Food–drug interactions. Drugs 62:1481–1502 (2002).

    Article  PubMed  CAS  Google Scholar 

  7. W. N. Charman, C. J. H. Porter, S. Mithani, and J. B. Dressman. Physicochemical and physiological mechanisms for the effects of food on drug absorption: the effects of lipids and pH. J. Pharm. Sci. 86:269–282 (1997).

    Article  PubMed  CAS  Google Scholar 

  8. D. Fleisher, C. Li, Y. Zhou, L. Pao, and A. Karim. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clin. Pharmacokinet. 36:233–254 (1999).

    Article  PubMed  CAS  Google Scholar 

  9. K. M. Cunningham, R. J. Baker, M. Horowitz, A. F. Maddox, M. A. Edelbroek, and B. E. Chatterton. Use of technetium-99m(V)thiocyanate to measure gastric emptying of fat. J. Nucl. Med. 32:878–881 (1991).

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. M. Fried, E. A. Mayer, J. B. Jansen, C. B. Lamers, I. L. Taylor, S. R. Bloom, and J. H. Meyer. Temporal relationships of cholecystokinin release, pancreatobiliary secretion, and gastric emptying of a mixed meal. Gastroenterology 95:1344–1350 (1988).

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  13. J. Glatzle, T. J. Kalogeris, T. T. Zittel, S. Guerrini, P. Tso, and H. E. Raybould. Chylomicron components mediate intestinal lipid-induced inhibition of gastric motor function. Am. J. Physiol. Gastrointest. Liver Physiol. 282:G86–G91 (2002).

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  16. S. M. Caliph, W. N. Charman, and C. J. H. Porter. 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).

    Article  PubMed  CAS  Google Scholar 

  17. B. G. Stone, H. J. Ansel, F. J. Peterson, and R. L. Gebhard. Gallbladder emptying stimuli in obese and normal-weight subjects. Hepatology 15:795–798 (1992).

    Article  PubMed  CAS  Google Scholar 

  18. F. Froehlich, J. J. Gonvers, and M. Fried. Role of nutrient fat and cholecystokinin in regulation of gallbladder emptying in man. Dig. Dis. Sci. 40:529–533 (1995).

    Article  PubMed  CAS  Google Scholar 

  19. O. Hernell, J. E. Staggers, and M. C. Carey. 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).

    Article  PubMed  CAS  Google Scholar 

  20. M. C. Carey, D. M. Small, and C. M. Bliss. Lipid digestion and absorption. Annu. Rev. Physiol. 45:651–677 (1983).

    Article  PubMed  CAS  Google Scholar 

  21. L. J. Naylor, V. Bakatselou, and J. B. Dressman. Comparison of the mechanism of dissolution of hydrocortisone in simple and mixed micelle systems. Pharm. Res. 10:865–870 (1993).

    Article  PubMed  CAS  Google Scholar 

  22. B. L. Pedersen, H. Brondsted, H. Lennernas, F. N. Christensen, A. Mullertz, and H. G. Kristensen. Dissolution of hydrocortisone in human and simulated intestinal fluids. Pharm. Res. 17:183–189 (2000).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  24. G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413–420 (1995).

    Article  PubMed  CAS  Google Scholar 

  25. J. N. Hunt and M. T. Knox. A relation between the chain length of fatty acids and the slowing of gastric emptying. J. Physiol. 194:327–336 (1968).

    PubMed  CAS  Google Scholar 

  26. S. D. Ladas, P. E. T. Isaacs, G. M. Murphy, and G. E. Sladen. 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).

    Article  PubMed  CAS  Google Scholar 

  27. E. M. Persson, A.-S. Gustafsson, A. S. Carlsson, R. G. Nilsson, L. Knutson, P. Forsell, G. Hanisch, H. Lennernas, and B. Abrahamsson. 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).

    Article  PubMed  CAS  Google Scholar 

  28. C. J. H. Porter, A. M. Kaukonen, B. J. Boyd, G. A. Edwards, and W. N. Charman. 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).

    Article  PubMed  CAS  Google Scholar 

  29. K. Kelly, B. O’Mahony, B. Lindsay, T. Jones, M. McDonagh, L. Martini, H. N. E. Stevens, and C. G. Wilson. The effect of long chain fatty acids on the gastric emptying of a co-administered tablet in fasted human volunteers. AAPS PharmSci. 4:T3072 (2002).

    Google Scholar 

  30. A. Rasyid and A. Lelo. The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. Aliment. Pharmacol. Ther. 13:245–249 (1999).

    Article  PubMed  CAS  Google Scholar 

  31. L. Kalantzi, T. Fuerst, B. Abrahamsson, K. Goumas, V. Kalioras, J. B. Dressman, and C. Reppas. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability studies in the fasting and in the fed state AAPS PharmSci. 5: R6068 (2003).

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  33. H. P. Porter and D. R. Saunders. Isolation of the aqueous phase of human intestinal contents during the digestion of a fatty meal. Gastroenterology 60:997–1007 (1971).

    PubMed  CAS  Google Scholar 

  34. L. Sek, C. J. H. Porter, A. M. Kaukonen, and W. N. Charman. Evaluation of the in-vitro digestion profiles of long and medium chain glycerides and the phase behaviour of their lipolytic products. J. Pharm. Pharmacol. 54:29–41 (2002).

    Article  PubMed  CAS  Google Scholar 

  35. S. Ellenbogen, S. A. Jenkins, J. S. Grime, M. Critchley, C. R. Mackie, and J. N. Baxter. Preduodenal mechanisms in initiating gallbladder emptying in man. Br. J. Surg. 75:940–945 (1988).

    Article  PubMed  CAS  Google Scholar 

  36. E. M. Persson, R. G. Nilsson, G. I. Hansson, L. J. Lofgren, F. Liback, L. Knutson, B. Abrahamsson, and H. Lennernas. 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).

    Article  PubMed  CAS  Google Scholar 

  37. P. Holzer. Gastrointestinal afferents as targets of novel drugs for the treatment of functional bowel disorders and visceral pain. Eur. J. Pharmacol. 429:177–193 (2001).

    Article  PubMed  CAS  Google Scholar 

  38. C. G. Wilson and K. Kelly. Gastrointestinal transit and drug absorption. In J. B. Dressman and J. Kramer (eds.), Pharmaceutical Dissolution Testing, Taylor and Francis, London, 2006, pp. 97–125.

    Google Scholar 

  39. C. J. H. Porter, N. L. Trevaskis, and W. N. Charman. Lipids and lipid based formulations: optimising the oral delivery of lipophilic drugs. Nat. Rev. Drug Discov. 6:231–248 (2007).

    Article  PubMed  CAS  Google Scholar 

  40. M. A. Edelbroek, M. Horowitz, A. F. Maddox, and J. Bellen. Gastric emptying and intragastric distribution of oil in the presence of a liquid or a solid meal. J. Nucl. Med. 33:1283–1290 (1992).

    PubMed  CAS  Google Scholar 

  41. N. Kaniwa, N. Aoyagi, H. Ogata, H. Motoyama, and H. Yasumi. Gastric emptying rates of drug preparations. II. Effects of size and density of enteric-coated drug preparations and food on gastric emptying rates in humans. J. Pharmacobio-Dyn. 11:571–575 (1988).

    PubMed  CAS  Google Scholar 

  42. R. L. Oberle, T. S. Chen, C. Lloyd, J. L. Barnett, C. Owyang, J. Meyer, and G. L. Amidon. The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids. Gastroenterology 99:1275–1282 (1990).

    PubMed  CAS  Google Scholar 

  43. C. L. Dobson, S. S. Davis, S. Chauhan, R. A. Sparrow, and I. R. Wilding. The effect of oleic acid on the human ileal brake and its implications for small intestinal transit of tablet formulations. Pharm. Res. 16:92–96 (1999).

    Article  PubMed  CAS  Google Scholar 

  44. C. L. Dobson, S. S. Davis, S. Chauhan, R. A. Sparrow, and I. R. Wilding. The effect of ileal brake activators on the oral bioavailability of atenolol in man. Int. J. Pharm. 248:61–70 (2002).

    Article  PubMed  CAS  Google Scholar 

  45. K. Fujimoto, J. A. Cardelli, and P. Tso. Increased apolipoprotein A-IV in rat mesenteric lymph after lipid meal acts as a physiological signal for satiation. Am. J. Physiol. 262:G1002–G1006 (1992).

    PubMed  CAS  Google Scholar 

  46. R. P. Jazrawi, P. Pazzi, M. L. Petrioni, N. Prandini, C. Paul, J. A. Adam, S. Gullini, and T. C. Northfield. Postprandial gallbladder motor function: refilling and turnover of bile in health and in cholelithiasis. Gastroenterology 109:582–591 (1995).

    Article  PubMed  CAS  Google Scholar 

  47. G. A. Kossena, B. J. Boyd, C. J. H. Porter, and W. N. Charman. 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).

    Article  PubMed  CAS  Google Scholar 

  48. G. A. Kossena, W. N. Charman, B. J. Boyd, D. E. Dunstan, and C. J. H. Porter. 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).

    Article  PubMed  CAS  Google Scholar 

  49. C. J. H. Porter, A. M. Kaukonen, A. Taillardat-Bertschinger, B. J. Boyd, J. M. O’Connor, G. A. Edwards, and W. N. Charman. 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).

    Article  PubMed  CAS  Google Scholar 

  50. G. A. Kossena, W. N. Charman, B. J. Boyd, and C. J. H. Porter. 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).

    Article  PubMed  CAS  Google Scholar 

  51. A. K. Trull, K. K. C. Tan, L. Tan, G. J. M. Alexander, and N. V. Jamieson. Enhanced absorption of new oral cyclosporin microemulsion formulation, Neoral, in liver transplant recipients with external biliary diversion. Transplant Proceedings 29:2977–2978 (1994).

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to GSK for financial support and to Dr. Paul Ingram and Kirsteen Wilson (Bio-Images Research Ltd) for analytical assistance. The co-ordination roles of Eilis O’Driscoll and Paul Linacre at GSK are also gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Melbourne, Victoria, 3052, Australia

    Greg A. Kossena, William N. Charman & Christopher J. H. Porter

  2. Strathclyde Institute of Pharmacy and Biomedical Sciences, Glasgow, G4 0NR, Scotland, UK

    Clive G. Wilson

  3. Bio-Images Research Ltd., Glasgow, G4 0SF, Scotland, UK

    Clive G. Wilson, Bridget O’Mahony & Blythe Lindsay

  4. GSK, New Frontiers South, Harlow, Essex, UK

    John M. Hempenstall & Christopher L. Davison

  5. GSK Upper Providence, Collegeville, Pennsylvania, USA

    Patrick J. Crowley

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  1. Greg A. Kossena
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  2. William N. Charman
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  3. Clive G. Wilson
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  4. Bridget O’Mahony
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  9. Christopher J. H. Porter
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Correspondence to Christopher J. H. Porter.

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Kossena, G.A., Charman, W.N., Wilson, C.G. et al. Low Dose Lipid Formulations: Effects on Gastric Emptying and Biliary Secretion. Pharm Res 24, 2084–2096 (2007). https://doi.org/10.1007/s11095-007-9363-8

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  • DOI: https://doi.org/10.1007/s11095-007-9363-8

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