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Pharmaceutical Research

, Volume 30, Issue 12, pp 3045–3058 | Cite as

Lipid Absorption Triggers Drug Supersaturation at the Intestinal Unstirred Water Layer and Promotes Drug Absorption from Mixed Micelles

  • Yan Yan Yeap
  • Natalie L. Trevaskis
  • Christopher J. H. Porter
Research Paper

Abstract

Purpose

To evaluate the potential for the acidic intestinal unstirred water layer (UWL) to induce drug supersaturation and enhance drug absorption from intestinal mixed micelles, via the promotion of fatty acid absorption.

Methods

Using a single-pass rat jejunal perfusion model, the absorptive-flux of cinnarizine and 3H-oleic acid from oleic acid-containing intestinal mixed micelles was assessed under normal acidic microclimate conditions and conditions where the acidic microclimate was attenuated via the co-administration of amiloride. As a control, the absorptive-flux of cinnarizine from micelles of Brij® 97 (a non-ionizable, non-absorbable surfactant) was assessed in the absence and presence of amiloride. Cinnarizine solubility was evaluated under conditions of decreasing pH and decreasing micellar lipid content to assess likely changes in solubilization and thermodynamic activity during micellar passage across the UWL.

Results

In the presence of amiloride, the absorptive-flux of cinnarizine and 3H-oleic acid from mixed micelles decreased 6.5-fold and 3.0-fold, respectively. In contrast, the absorptive-flux of cinnarizine from Brij® 97 micelles remained unchanged by amiloride, and was significantly lower than from the long-chain micelles. Cinnarizine solubility in long-chain micelles decreased under conditions where pH and micellar lipid content decreased simultaneously.

Conclusions

The acidic microclimate of the intestinal UWL promotes drug absorption from intestinal mixed micelles via the promotion of fatty acid absorption which subsequently stimulates drug supersaturation. The observations suggest that formulations (or food) containing absorbable lipids (or their digestive precursors) may outperform formulations that lack absorbable components since the latter do not benefit from lipid absorption-induced drug supersaturation.

Key words

absorption food effect lipid based formulations poorly water soluble drug supersaturation unstirred water layer 

ABBREVIATIONS

CD36

Cluster of Differentiation 36

CIN

cinnarizine

FATP

fatty acid transport protein

GI

gastrointestinal

HPLC

high performance liquid chromatography

LBF

Lipid based formulation

LCFA

long-chain fatty acid

LFCS

Lipid Formulation Classification System

LPC

L-α-lysophosphatidylcholine

OA

oleic acid

PWSD

poorly water-soluble drugs

SEIF

simulated endogenous intestinal fluid

SR-BI

Scavenger Receptor Class B Type I

UWL

unstirred water layer

Notes

Acknowledgments and Disclosures

Funding support from the National Health and Medical Research Council (NHMRC) of Australia is gratefully acknowledged.

Supplementary material

11095_2013_1104_MOESM1_ESM.docx (3.1 mb)
ESM 1 (DOCX 3.14 mb)

References

  1. 1.
    Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65(1):315–499.PubMedCrossRefGoogle Scholar
  2. 2.
    Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007;6(3):231–48.PubMedCrossRefGoogle Scholar
  3. 3.
    Poelma FGJ, Breäs R, Tukker JJ, Crommelin DJA. Intestinal absorption of drugs. The influence of mixed micelles on the disappearance kinetics of drugs from the small intestine of the rat. J Pharm Pharmacol. 1991;43(5):317–24.PubMedCrossRefGoogle Scholar
  4. 4.
    Amidon GE, Higuchi WI, Ho NFH. Theoretical and experimental studies of transport of micelle-solubilized solutes. J Pharm Sci. 1982;71(1):77–84.PubMedCrossRefGoogle Scholar
  5. 5.
    Miller JM, Beig A, Krieg BJ, Carr RA, Borchardt TB, Amidon GE, et al. The solubility–permeability interplay: mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation. Mol Pharm. 2011;8(5):1848–56.PubMedCrossRefGoogle Scholar
  6. 6.
    Dahan A, Miller JM, Hoffman A, Amidon GE, Amidon GL. The solubility–permeability interplay in using cyclodextrins as pharmaceutical solubilizers: mechanistic modeling and application to progesterone. J Pharm Sci. 2010;99(6):2739–49.PubMedGoogle Scholar
  7. 7.
    Anby MU, Williams HD, McIntosh M, Benameur H, Edwards GA, Pouton CW, et al. Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems. Mol Pharm. 2012;9(7):2063–79.CrossRefGoogle Scholar
  8. 8.
    Williams HD, Anby MU, Sassene P, Kleberg K, Bakala-N’Goma J-C, Calderone M, et al. Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of Type I, II, IIIA, IIIB, and IV formulations during in vitro digestion. Mol Pharm. 2012;9(11):3286–300.PubMedCrossRefGoogle Scholar
  9. 9.
    Williams HD, Sassene P, Kleberg K, Calderone M, Igonin A, Jule E, et al. Toward the establishment of standardized in vitro tests for lipid-based formulations: 3) Understanding supersaturation versus precipitation potential during the in vitro digestion of Type I, II, IIIA, IIIB and IV lipid-based formulations. Pharmaceutical Research. 2013. doi: 10.1007/s11095-013-1038-z.
  10. 10.
    Yeap YY, Trevaskis NL, Quach T, Tso P, Charman WN, Porter CJH. Bile secretion promotes drug absorption from lipid colloidal phases via induction of supersaturation. Mol Pharm. 2013;10:1874–89.PubMedCrossRefGoogle Scholar
  11. 11.
    Yeap YY, Trevaskis NL, Porter CJH. The potential for drug supersaturation during intestinal processing of lipid-based formulations may be enhanced for basic drugs. Molecular Pharmaceutics. 2013. doi:  10.1021/mp400035z.
  12. 12.
    Mohsin K, Long MA, Pouton CW. Design of lipid-based formulations for oral administration of poorly water-soluble drugs: precipitation of drug after dispersion of formulations in aqueous solution. J Pharm Sci. 2009;98(10):3582–95.PubMedCrossRefGoogle Scholar
  13. 13.
    Gao P, Morozowich W. Development of supersaturatable self-emulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs. Expert Opin Drug Deliv. 2006;3(1):97–110.PubMedCrossRefGoogle Scholar
  14. 14.
    Gao P, Rush BD, Pfund WP, Huang T, Bauer JM, Morozowich W, et al. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J Pharm Sci. 2003;92(12):2386–98.PubMedCrossRefGoogle Scholar
  15. 15.
    Kaukonen AM, Boyd B, Porter C, Charman W. Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharm Res. 2004;21(2):245–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Lucas ML, Schneider W, Haberich FJ, Blair JA. Direct measurement by pH-microelectrode of the pH microclimate in rat proximal jejunum. Proc R Soc London, Ser B. 1975;192(1106):39–48.CrossRefGoogle Scholar
  17. 17.
    Shiau YF, Fernandez P, Jackson MJ, McMonagle S. Mechanisms maintaining a low-pH microclimate in the intestine. Am J Physiol Gastrointest Liver Physiol. 1985;248(6):G608–17.Google Scholar
  18. 18.
    Ikuma M, Hanai H, Kaneko E, Hayashi H, Hoshi T. Effects of aging on the microclimate pH of the rat jejunum. Biochim Biophys Acta (BBA) Biomembr. 1996;1280(1):19–26.CrossRefGoogle Scholar
  19. 19.
    Shiau YF, Kelemen RJ, Reed MA. Acidic mucin layer facilitates micelle dissociation and fatty acid diffusion. Am J Physiol Gastrointest Liver Physiol. 1990;259(4):G671–5.Google Scholar
  20. 20.
    Shiau YF. Mechanism of intestinal fatty acid uptake in the rat: the role of an acidic microclimate. J Physiol. 1990;421(1):463–74.PubMedGoogle Scholar
  21. 21.
    Li C-Y, Zimmerman CL, Wiedmann TS. Diffusivity of bile salt/phospholipid aggregates in mucin. Pharm Res. 1996;13(4):535–41.PubMedCrossRefGoogle Scholar
  22. 22.
    Khanvilkar K, Donovan MD, Flanagan DR. Drug transfer through mucus. Adv Drug Deliv Rev. 2001;48(2–3):173–93.PubMedCrossRefGoogle Scholar
  23. 23.
    Kossena GA, Charman WN, Boyd BJ, Dunstan DE, Porter CJH. Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems: a phase diagram approach. J Pharm Sci. 2004;93(2):332–48.PubMedCrossRefGoogle Scholar
  24. 24.
    Mahnensmith RL, Aronson PS. The plasma membrane sodium-hydrogen exchanger and its role in physiological and pathophysiological processes. Circ Res. 1985;56(6):773–88.PubMedCrossRefGoogle Scholar
  25. 25.
    Williams HD, Sassene P, Kleberg K, Bakala-N'Goma J-C, Calderone M, Jannin V, et al. Toward the establishment of standardized in vitro tests for lipid-based formulations, part 1: method parameterization and comparison of in vitro digestion profiles across a range of representative formulations. J Pharm Sci. 2012;101(9):3360–80.PubMedCrossRefGoogle Scholar
  26. 26.
    Winne D. Rat jejunum perfused in situ: effect of perfusion rate and intraluminal radius on absorption rate and effective unstirred layer thickness. Naunyn Schmiedeberg’s Arch Pharmacol. 1979;307(3):265–74.CrossRefGoogle Scholar
  27. 27.
    Cummins CL, Salphati L, Reid MJ, Benet LZ. In vivo modulation of intestinal CYP3A metabolism by P-glycoprotein: studies using the rat single-pass intestinal perfusion model. J Pharmacol Exp Ther. 2003;305(1):306–14.PubMedCrossRefGoogle Scholar
  28. 28.
    Johnson BM, Chen W, Borchardt RT, Charman WN, Porter CJH. A kinetic evaluation of the absorption, efflux, and metabolism of verapamil in the autoperfused rat jejunum. J Pharmacol Exp Ther. 2003;305(1):151–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Westergaard H, Dietschy JM. The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell. J Clin Investig. 1976;58(1):97–108.PubMedCrossRefGoogle Scholar
  30. 30.
    Nassir F, Wilson B, Han X, Gross RW, Abumrad NA. CD36 is important for fatty acid and cholesterol uptake by the proximal but not distal intestine. J Biol Chem. 2007;282(27):19493–501.PubMedCrossRefGoogle Scholar
  31. 31.
    Stahl A, Hirsch DJ, Gimeno RE, Punreddy S, Ge P, Watson N, et al. Identification of the major intestinal fatty acid transport protein. Mol Cell. 1999;4(3):299–308.PubMedCrossRefGoogle Scholar
  32. 32.
    Bietrix F, Yan D, Nauze M, Rolland C, Bertrand-Michel J, Coméra C, et al. Accelerated lipid absorption in mice overexpressing intestinal SR-BI. J Biol Chem. 2006;281(11):7214–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Chow SL, Hollander D. A dual, concentration-dependent absorption mechanism of linoleic acid by rat jejunum in vitro. J Lipid Res. 1979;20(3):349–56.PubMedGoogle Scholar
  34. 34.
    Chow SL, Hollander D. Linoleic acid absorption in the unaesthetized rat: mechanism of transport and influence of luminal factors on absorption. Lipids. 1979;14(4):378–85.PubMedCrossRefGoogle Scholar
  35. 35.
    Ling K-Y, Lee H-Y, Hollander D. Mechanisms of linoleic acid uptake by rabbit small intestinal brush border membrane vesicles. Lipids. 1989;24(1):51–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Stremmel W. Uptake of fatty acids by jejunal mucosal cells is mediated by a fatty acid binding membrane protein. J Clin Investig. 1988;82(6):2001–10.PubMedCrossRefGoogle Scholar
  37. 37.
    Goré J, Hoinard C, Couet C. Linoleic acid uptake by isolated enterocytes: influence of α-linolenic acid on absorption. Lipids. 1994;29(10):701–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Kanicky JR, Shah DO. Effect of degree, type, and position of unsaturation on the pKa of long-chain fatty acids. J Colloid Interface Sci. 2002;256(1):201–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Hofmann AF. Molecular association in fat digestion. Molecular Association in Biological and Related Systems: American Chemical Society; 1968. p. 53–66.Google Scholar
  40. 40.
    Hofmann AF, Mysels KJ. Bile salts as biological surfactants. Colloids Surf. 1987;30(1):145–73.CrossRefGoogle Scholar
  41. 41.
    Schoeller C, Keelan M, Mulvey G, Stremmel W, Thomson ABR. Oleic acid uptake into rat and rabbit jejunal brush border membrane. Biochim Biophys Acta (BBA) Biomembr. 1995;1236(1):51–64.CrossRefGoogle Scholar
  42. 42.
    Cuiné JF, McEvoy CL, Charman WN, Pouton CW, Edwards GA, Benameur H, et al. Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs. J Pharm Sci. 2008;97(2):995–1012.PubMedCrossRefGoogle Scholar
  43. 43.
    Kossena GA, Charman WN, Boyd BJ, Porter CJH. Influence of the intermediate digestion phases of common formulation lipids on the absorption of a poorly water-soluble drug. J Pharm Sci. 2005;94(3):481–92.PubMedCrossRefGoogle Scholar
  44. 44.
    Williams HD, Trevaskis NL, Pouton CW, Porter CJH. Lipid-based formulations and drug supersaturation: Harnessing the unique benefits of the lipid digestion/absorption pathway. Pharm Res. 2013 (in press, this issue).Google Scholar
  45. 45.
    Bevernage J, Brouwers J, Annaert P, Augustijns P. Drug precipitation–permeation interplay: supersaturation in an absorptive environment. Eur J Pharm Biopharm. 2012;82(2):424–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Raghavan SL, Trividic A, Davis AF, Hadgraft J. Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm. 2001;212(2):213–21.PubMedCrossRefGoogle Scholar
  47. 47.
    Machefer S, Huddar MM, Schnitzlein K. Effect of polymer admixtures on the growth habit of ionic crystals. Study on crystal growth kinetics of potassium dihydrogen phosphate in water/polyol mixtures. J Cryst Growth. 2008;310(24):5347–56.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleAustralia

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