Transfer of lipophilic drugs between liposomal membranes and biological interfaces: consequences for drug delivery
Abstract
This review paper describes the present knowledge on the interaction of lipophilic, poorly water soluble, drugs with liposomal membranes and the reversibility of this interaction. This interaction is discussed in the context of equilibrium and spontaneous transfer kinetics of the drug, when the liposomes are brought in co-dispersion with other artificial or natural phospholipid membranes in an aqueous medium. The focus is on drugs, which have the potential to partition (dissolve) in a lipid membrane but do not perturb membranes. The degree of interaction is described as solubility of a drug in phospholipid membranes and the kinetics of transfer of a lipophilic drug between membranes. Finally, the consequences of these two factors on the design of lipid based carriers for oral, as well as parenteral use, for lipophilic drugs and lead selection of oral lipophilic drugs is described. Since liposomes serve as model-membranes for natural membranes, the assessment of lipid solubility and transfer kinetics of lipophilic drug using liposome formulations may additionally have predictive value for bioavailability and biodistribution and the pharmacokinetics of lipophilic drugs after parenteral as well as oral administration.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The difference in release profiles under the two conditions can be attributed to bilayer exchange.
“The difference in release profiles under the two conditions can be attributed to bilayer exchange, which has been reported for a variety of lipophilic, poorly water soluble drugs that partition into the liposomal bilayer, as reviewed by Fahr and colleagues46.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [46]
Cites
Amidon, G. L., Lennernäs, H., Shah, V. P., & Crison, J. R. (1995) · Pharmaceutical Research · doi:10.1023/a:1016212804288 · Cited by 5,430 · see citing works
The Hydrophobic Effect: Formation of Micelles and Biological Membranes
Tanford, C. (1991) · Medical Entomology and Zoology · Cited by 3,331 · see citing works
The Hydrophobic Effect: Formation of Micelles and Biological Membranes
Walker, C. H. (1981) · FEBS Letters · doi:10.1016/0014-5793(81)80071-3 · Cited by 2,712 · see citing works
Liposomes: From Physics to Applications
Lasiç, D. D. (1993) · Cited by 1,304 · see citing works
Theory of self-assembly of lipid bilayers and vesicles
Israelachvili, J. N., Mitchell, D. J., & Ninham, B. W. (1977) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(77)90099-2 · Cited by 961 · see citing works
Engineering liposomes for drug delivery: progress and problems
Gregoriadis, G. C. (1995) · Trends in biotechnology · doi:10.1016/s0167-7799(00)89017-4 · Cited by 626 · see citing works
Ligand-targeted liposomal anticancer drugs
Sapra, P., & Allen, T. M. (2003) · Progress in Lipid Research · doi:10.1016/s0163-7827(03)00032-8 · Cited by 438 · see citing works
In vitro assessment of oral lipid based formulations
Porter, C. J. H., & Charman, W. N. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(01)00182-x · Cited by 392 · see citing works
Mechanism of cholesterol and phosphatidylcholine exchange or transfer between unilamellar vesicles
McLean, L. R., & Phillips, M. C. (1981) · Biochemistry · doi:10.1021/bi00513a028 · Cited by 352 · see citing works
Movement of fatty acids, fatty acid analogs, and bile acids across phospholipid bilayers
Kamp, F., & Hamilton, J. A. (1993) · Biochemistry · doi:10.1021/bi00092a017 · Cited by 310 · see citing works
Fatty Acid Flip-Flop in Phospholipid Bilayers Is Extremely Fast
Kamp, F., Zakim, D., Zhang, F., Noy, N., & Hamilton, J. A. (1995) · Biochemistry · doi:10.1021/bi00037a034 · Cited by 292 · see citing works
Huang, S. K., Mayhew, E. G., Gilani, S., Lasiç, D. D., Martin, F. J., & Papahadjopoulos, D. (1992) · PubMed · Cited by 274 · see citing works
Gabizón, A., Dagan, A., Goren, D., Barenholz, Y., & FUKS, Z. Y. (1982) · PubMed · Cited by 263 · see citing works
Scherphof, G. L., Roerdink, F. H., Waite, M. B., & Parks, J. S. (1978) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(78)90025-9 · Cited by 246 · see citing works
Bai, J., & Pagano, R. E. (1997) · Biochemistry · doi:10.1021/bi970145r · Cited by 229 · see citing works
Influence of molecular packing and phospholipid type on rates of cholesterol exchange
Lund‐Katz, S., Laboda, H. M., McLean, L. R., & Phillips, M. C. (1988) · Biochemistry · doi:10.1021/bi00409a044 · Cited by 224 · see citing works
Free-energy determinants of alpha-helix insertion into lipid bilayers
Ben‐Tal, N., Ben‐Shaul, A., Nicholls, A. O., & Honig, B. H. (1996) · Biophysical Journal · doi:10.1016/s0006-3495(96)79744-8 · Cited by 219 · see citing works
Liposomes: Applications in Medicine
Banerjee, R. (2001) · Journal of Biomaterials Applications · doi:10.1106/ra7u-1v9c-rv7c-8qxl · Cited by 213 · see citing works
Kossena, G. A., Boyd, B. J., Porter, C. J. H., & Charman, W. N. (2003) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.10329 · Cited by 199 · see citing works
Characterization, toxicity and therapeutic efficacy of adrïamycin encapsulated in liposomes
Olson, F. C., Mayhew, E. G., Maslow, D. E., et al. (1982) · European Journal of Cancer and Clinical Oncology · doi:10.1016/0277-5379(82)90060-8 · Cited by 180 · see citing works
From Conventional to Stealth Liposomes a new Frontier in Cancer Chemotherapy
Cattel, L., Ceruti, M., & Dosio, F. (2003) · Tumori Journal · doi:10.1177/030089160308900302 · Cited by 175 · see citing works
Transfer of long-chain fluorescent free fatty acids between unilamellar vesicles
Storch, J., & Kleinfeld, A. M. (1986) · Biochemistry · doi:10.1021/bi00355a041 · Cited by 157 · see citing works
Almog, S., Kushnir, T., Nir, S., et al. (1986) · Biochemistry · doi:10.1021/bi00357a048 · Cited by 143 · see citing works
van Hoogevest, P., & KRUIJFF, B. D. (1978) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(78)90276-6 · Cited by 141 · see citing works
Self-citationKinetics of phosphatidylcholine and lysophosphatidylcholine exchange between unilamellar vesicles
McLean, L. R., & Phillips, M. C. (1984) · Biochemistry · doi:10.1021/bi00315a017 · Cited by 141 · see citing works
Simulation studies of the interaction of antimicrobial peptides and lipid bilayers
Rocca, P. L., Biggin, P. C., Tieleman, D. P., et al. (1999) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/s0005-2736(99)00206-0 · Cited by 136 · see citing works
Modulation of the orientational order profile of the lipid acyl chain in the L? phase
Lafleur, M., Cullis, P. R., & Bloom, M. J. (1990) · European Biophysics Journal · doi:10.1007/bf00185086 · Cited by 126 · see citing works
Movement of cholesterol between vesicles prepared with different phospholipids or sizes.
Fugler, L., Clejan, S., & Bittman, R. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)89236-5 · Cited by 119 · see citing works
Transfer of oleic acid between albumin and phospholipid vesicles.
Hamilton, J. A., & Cistola, D. P. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.1.82 · Cited by 118 · see citing works
Mechanism of the selective toxicity of amphotericin B incorporated into liposomes.
Juliano, R. L., Grant, C. W. M., Barber, K. R., & Kalp, M. A. (1987) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)10311-8 · Cited by 118 · see citing works
Dissociation of Long and Very Long Chain Fatty Acids from Phospholipid Bilayers
Zhang, F., Kamp, F., & Hamilton, J. A. (1996) · Biochemistry · doi:10.1021/bi961685b · Cited by 115 · see citing works
Mayer, L. D., Bally, M. B., Loughrey, H. C., Masin, D., & Cullis, P. R. (1990) · PubMed · Cited by 111 · see citing works
Lennernäs, H. (1995) · Pharmaceutical Research · doi:10.1023/a:1016220428705 · Cited by 106 · see citing works
Spontaneous phosphatidylcholine transfer by collision between vesicles at high lipid concentration
Jones, J., & Thompson, T. E. (1989) · Biochemistry · doi:10.1021/bi00427a019 · Cited by 106 · see citing works
Allison, B., Waterfield, E. M., Richter, A. M., et al. (1991) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.1991.tb02079.x · Cited by 104 · see citing works
Comparative in vivo studies with paclitaxel and liposome-encapsulated paclitaxel.
Cabanes, A., Briggs, K., Gokhale, P. C., Treat, J., & Rahman, A. (1998) · International Journal of Oncology · doi:10.3892/ijo.12.5.1035 · Cited by 103 · see citing works
Kleinfeld, A. M., Chu, P., & Romero, C. (1997) · Biochemistry · doi:10.1021/bi971440e · Cited by 102 · see citing works
An activation-collision mechanism for cholesterol transfer between membranes.
Steck, T. L., Kézdy, F. J., & Lange, Y. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)37666-x · Cited by 100 · see citing works
Paclitaxel Partitioning into Lipid Bilayers
Wenk, M. R., Fahr, A., Reszka, R. C., et al. (1996) · Journal of Pharmaceutical Sciences · doi:10.1021/js950120i · Cited by 96 · see citing works
Self-citationWasan, K. M., Brazeau, G. A., Keyhani, A., et al. (1993) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.37.2.246 · Cited by 90 · see citing works
The Permeability of Plaut Protoplasts to Small Molecules
Collander, R. (1949) · Physiologia Plantarum · doi:10.1111/j.1399-3054.1949.tb07655.x · Cited by 89 · see citing works
Allison, B., Pritchard, P. H., Richter, A. M., et al. (1990) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.1990.tb01792.x · Cited by 84 · see citing works
SOLVATION: HOW TO OBTAIN MICROSCOPIC ENERGIES FROM PARTITIONING AND SOLVATION EXPERIMENTS
Chan, H. S., & Dill, K. A. (1997) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.biophys.26.1.425 · Cited by 83 · see citing works
On the mechanism of transfer of cholesterol between human erythrocytes and plasma.
Lange, Y., Molinaro, A. L., Chauncey, T. R., et al. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)32311-1 · Cited by 82 · see citing works
Schwendener, R. A., & Schott, H. N. (1996) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/bf01209119 · Cited by 79 · see citing works
Gatti, G., & Perucca, E. (1994) · PubMed · Cited by 73 · see citing works
Perturbation of a lipid membrane by amphipathic peptides and its role in pore formation
Zemel, A., Ben‐Shaul, A., & May, S. (2004) · European Biophysics Journal · doi:10.1007/s00249-004-0445-9 · Cited by 73 · see citing works
Self-citationIsele, U., Schieweck, K., Kessler, R., et al. (1995) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600840209 · Cited by 69 · see citing works
Mansilha, C., Gameiro, P., PRIETO, M. J. E., & de Castro, B. (2003) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(02)00528-7 · Cited by 66 · see citing works
Drug release characteristics of lipid based benzoporphyrin derivative.
Chowdhary, R. K., Shariff, I., & Dolphin, D. (2003) · PubMed · Cited by 65 · see citing works
Inactive fatty acids are unable to flip‐flop across the lipid bilayer
Ježek, P., Modrianský, M., & Garlid, K. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00334-7 · Cited by 64 · see citing works
Bar, L. K., Barenholz, Y., & Thompson, T. E. (1987) · Biochemistry · doi:10.1021/bi00391a037 · Cited by 63 · see citing works
Hunt, C. A. (1982) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(82)90233-1 · Cited by 61 · see citing works
Transfer of long-chain fluorescent fatty acids between small and large unilamellar vesicles
Kleinfeld, A. M., & Storch, J. (1993) · Biochemistry · doi:10.1021/bi00059a024 · Cited by 58 · see citing works
A fluorescence and radiolabel study of sterol exchange between membranes
Nemecz, G., Fontaine, R. N., & Schroeder, F. (1988) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(88)90384-7 · Cited by 58 · see citing works
Changes of Intrinsic Membrane Potentials Induced by Flip-Flop of Long-Chain Fatty Acids
Pohl, E. E., Peterson, U., Sun, J., et al. (2000) · Biochemistry · doi:10.1021/bi9919549 · Cited by 57 · see citing works
A molecular model for lipid-mediated interaction between proteins in membranes
May, S., & Ben‐Shaul, A. (2000) · Physical Chemistry Chemical Physics · doi:10.1039/b003570j · Cited by 54 · see citing works
Self-citationMembrane Perturbation Induced by Interfacially Adsorbed Peptides
Zemel, A., Ben‐Shaul, A., & May, S. (2004) · Biophysical Journal · doi:10.1529/biophysj.103.033605 · Cited by 53 · see citing works
Self-citationBar, L. K., Barenholz, Y., & Thompson, T. E. (1986) · Biochemistry · doi:10.1021/bi00369a056 · Cited by 53 · see citing works
Schote, U., Ganz, P., Fahr, A., et al. (2002) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.10071 · Cited by 48 · see citing works
Self-citationAbsorption of Monoacylglycerols by Small Intestinal Brush Border Membrane
Schulthess, G., Lipka, G., Compassi, S., Boffelli, D., Weber, F. E., Paltauf, F., & Hauser, H. (1994) · Biochemistry · doi:10.1021/bi00181a009 · Cited by 47 · see citing works
Isele, U., van Hoogevest, P., Hilfiker, R., Capraro, H., Schieweck, K., & Leuenberger, H. (1994) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600831117 · Cited by 46 · see citing works
Self-citationNichols, J. L. (1988) · Biochemistry · doi:10.1021/bi00406a014 · Cited by 44 · see citing works
Kleinfeld, A. M., Chu, P., & Storch, J. (1997) · Biochemistry · doi:10.1021/bi962007s · Cited by 44 · see citing works
Guo, J., Ping, Q. N., & Chen, Y. (2001) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(00)00680-3 · Cited by 43 · see citing works
Factors affecting the encapsulation of drugs within liposomes
Stamp, D., & Juliano, R. L. (1979) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y79-081 · Cited by 42 · see citing works
Chowdhary, R. K., Sharif, I., Chansarkar, N., et al. (2003) · PubMed · Cited by 41 · see citing works
Liposomal Formulations of Cyclosporin A: Influence of Lipid Type and Dose on Pharmacokinetics
Fahr, A., Holz, M., & Fricker, G. (1995) · Pharmaceutical Research · doi:10.1023/a:1016220211925 · Cited by 37 · see citing works
Self-citationVerreck, G., Vandecruys, R., Conde, V. D., et al. (2004) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20028 · Cited by 36 · see citing works
Seelig, J., & Fahr, A. (2001) · Critical Reviews in Therapeutic Drug Carrier Systems · doi:10.1615/critrevtherdrugcarriersyst.v18.i2.10 · Cited by 25 · see citing works
Self-citationvan Etten, E. W. M., Stearne-Cullen, L. E. T., ten Kate, M. T., et al. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.3.540-545.2000 · Cited by 25 · see citing works
Carlson, R. P., Hartman, D. A., Ochalski, S. J., et al. (1998) · Inflammation Research · doi:10.1007/s000110050339 · Cited by 24 · see citing works
A laser-T-jump study of the adsorption of dipolar molecules to planar lipid membranes
Awiszus, R., & Stark, G. (1988) · European Biophysics Journal · doi:10.1007/bf00256481 · Cited by 24 · see citing works
Killion, J. J., & Fidler, I. J. (1994) · ImmunoMethods · doi:10.1006/immu.1994.1029 · Cited by 22 · see citing works
Go, M., & NGIAM, T.-L. (1997) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.45.2055 · Cited by 22 · see citing works
In vitro interaction of zinc(II)-phthalocyanine-containing liposomes and plasma lipoproteins
Rensen, P. C. N., Love, W. G., & Taylor, P. W. (1994) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/1011-1344(94)85033-x · Cited by 21 · see citing works
Membrane‐to‐Membrane Transfer of Lipophilic Drugs Used against Cancer or Infectious Diseasea
Juliano, R. L., Daoud, S. S., Krause, H.-J., et al. (1987) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1987.tb45794.x · Cited by 19 · see citing works
Bolard, J. (1986) · PubMed · Cited by 19 · see citing works
Liposomes as formulation excipients for protein pharmaceuticals: a model protein study.
Balasubramanian, S. V., Bruenn, J. A., & Straubinger, R. M. (2000) · Pharmaceutical Research · doi:10.1023/a:1007561308498 · Cited by 18 · see citing works
Mechanism of intermembrane phosphatidylcholine transfer: Effects of pH and membrane configuration
Yang, E., & Huestis, W. H. (1993) · Biochemistry · doi:10.1021/bi00096a035 · Cited by 18 · see citing works
A laser-T-jump study of the adsorption of dipolar molecules to planar lipid membranes
Awiszus, R., & Stark, G. (1988) · European Biophysics Journal · doi:10.1007/bf00254719 · Cited by 17 · see citing works
Calorimetric Evidence of Differentiated Transport of Limonin and Nomilin through Biomembranes
Castelli, F., Giuffrida, N., Tringali, C., et al. (2000) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf991282t · Cited by 16 · see citing works
In Vitro and In Vivo Studies Evaluating a Liposome System for Drug Solubilization
Lidgate, D. M., Feigner, P. L., Fleitman, J. S., et al. (1988) · Pharmaceutical Research · doi:10.1023/a:1015932600634 · Cited by 15 · see citing works
Cellular localization of stable solid liposomes in the liver of rats
Gotfredsen, C. F., van Berkel, T. J. C., Kruijt, J. K., et al. (1983) · Biochemical Pharmacology · doi:10.1016/0006-2952(83)90367-2 · Cited by 13 · see citing works
Fahr, A., Nimmerfall, F., & Wenger, R. M. (1994) · PubMed · Cited by 11 · see citing works
Self-citationFahr, A., & Reiter, G. (1999) · Cellular & Molecular Biology Letters · Cited by 10 · see citing works
Self-citationHosokawa, T., Yamauchi, M., Yamamoto, Y., et al. (2002) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.25.492 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Bailey, C. M., Liu, Y., Peng, G., Zhang, H., He, M., Sun, D., Zheng, P., Liu, Y., & Wang, Y. (2020) · Nanomedicine: Nanotechnology, Biology and Medicine · doi:10.1016/j.nano.2020.102278 · Cited by 44 · see citing works
- Authors
- Fahr, A., Hoogevest, P. V., May, S., Bergstrand, N., & S. Leigh, M. L.
- Affiliations
- Friedrich Schiller University Jena (DE)
- University of Basel (CH)
- North Dakota State University (US)
- Corresponding author
- Fahr, Alfred
- Venue
- European Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2005-11
- Volume
- 26
- Issue
- 3-4
- Pages
- 251-265
- ISSN
- 0928-0987 (ISSN-L)
- OpenAlex
- W1980057974
- Cited by
- 189
- References
- 87
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 8 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 10 · 2019: 7 · 2018: 9 · 2017: 6 · 2016: 7 · 2015: 14 · 2014: 13 · 2013: 14 · 2012: 7
- FWCI
- 7.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Wyeth Pharmaceuticals
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- lipophilic drugs, poorly water-soluble drugs, liposomal membranes, drug-membrane interactions, phospholipid membranes, lipid solubility, liposomes, lipid-based drug carriers, oral drug delivery, parenteral drug delivery, bioavailability, tissue distribution, pharmacokinetics
- MeSH terms
- Amphotericin B, Chemistry, Pharmaceutical, Pharmaceutical Preparations, Liposomes, Solubility, Thermodynamics, Cyclosporine, Paclitaxel
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review