Abstract
Purpose
To explore the effect of the nutritional state on the solubilizing properties of human intestinal fluids (HIF) on a time-after-food administration basis.
Methods
HIF were collected in fractions of 30 min from five volunteers in the fasted, fed and fat-enriched fed state. In vitro solubility of five BCS class II drugs (danazol, diazepam, nifedipine, ketoconazole, indomethacin) was assessed in the intestinal fractions and simulated intestinal fluids.
Results
Solubilities in intestinal fractions were characterized by high time- and subject-dependent variability. For the non-ionized drugs, solubility in early intestinal fractions was higher in both fed states compared to the fasted state, and in the fat-enriched fed state compared to the fed state. Solubility in simulated intestinal fluids did not sufficiently predict the solubilizing capacity of the early postprandial phase. Solubility in HIF was shown to be determined by a complex interplay of various intraluminal parameters. For the ionized drugs, pH played a significant role for indomethacin (R 2 = 0.86); for the partly ionized ketoconazole other intraluminal parameters were also important.
Conclusions
Solubilizing capacity of HIF in the fed state is strongly time-dependent. Intraluminal dissolution may, therefore, vary with drug arrival time in the small intestine and constitute a source of variability in intestinal drug absorption.
Similar content being viewed by others
Abbreviations
- BCS:
-
Biopharmaceutics Classification System
- FaSSIF:
-
fasted state simulated intestinal fluid
- FeSSIF:
-
fed state simulated intestinal fluid
- FeSSIF v2:
-
fed state simulated intestinal fluid version 2
- HIF:
-
human intestinal fluids
- MLR:
-
multiple linear regression
References
V. H. Sunesen, R. Vedelsdal, H. G. Kristensen, L. Christrup, and A. Müllertz. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug. Eur J Pharm Sci. 24:297–303 (2005). doi:10.1016/j.ejps.2004.11.005.
C. J. H. Porter, N. L. Trevaskis, and W. N. Charman. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 6:231–248 (2007). doi:10.1038/nrd2197.
J. Brouwers, J. Tack, and P. Augustijns. Parallel monitoring of plasma and intraluminal drug concentrations in man after oral administration of fosamprenavir in the fasted and fed state. Pharm Res. 24:1862–1869 (2007). doi:10.1007/s11095-007-9307-3.
J. Brouwers, J. Tack, F. Lammert, and P. Augustijns. Intraluminal drug and formulation behavior and integration in in vitro permeability estimation: a case study with amprenavir. J Pharm Sci. 95:372–383 (2006). doi:10.1002/jps.20553.
J. Brouwers, F. Ingels, J. Tack, and P. Augustijns. Determination of intraluminal theophylline concentrations after oral intake of an immediate- and a slow-release dosage form. J Pharm Pharmacol. 57:987–996 (2005). doi:10.1211/0022357056631.
E. Galia, E. Nicolaides, D. Hörter, R. Löbenberg, C. Reppas, and J. B. Dressman. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res. 15:698–705 (1998). doi:10.1023/A:1011910801212.
L. Kalantzi, E. Persson, B. Polentarutti, B. Abrahamsson, K. Goumas, J. B. Dressman, and C. Reppas. 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). doi:10.1007/s11095-006-0207-8.
E. M. Persson, A. Gustafsson, A. S. Carlsson, R. G. Nilsson, L. Knutson, P. Forsell, G. Hanisch, H. Lennernäs, 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). doi:10.1007/s11095-005-8192-x.
E. Jantratid, N. Janssen, C. Reppas, and J. B. Dressman. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharm Res. 25:1663–1676 (2008). doi:10.1007/s11095-008-9569-4.
L. Kalantzi, K. Goumas, V. Kalioras, B. Abrahamsson, J. B. Dressman, and C. Reppas. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharm Res. 23:165–176 (2006). doi:10.1007/s11095-005-8476-1.
S. Clarysse, J. Tack, F. Lammert, G. Duchateau, C. Reppas, and P. Augustijns. Postprandial evolution in composition and characteristics of human duodenal fluids in different nutritional states. J Pharm Sci. 98:1177–1192 (2008).
M. Vertzoni, N. Fotaki, E. Kostewicz, E. Stippler, C. Leuner, E. Nicolaides, J. Dressman, and C. Reppas. Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects. J Pharm Pharmacol. 56:453–462 (2004). doi:10.1211/0022357022935.
B. L. Pedersen, A. Müllertz, H. Brøndsted, and H. G. Kristensen. A comparison of the solubility of danazol in human and simulated gastrointestinal fluids. Pharm Res. 17:891–894 (2000). doi:10.1023/A:1007576713216.
S. D. Mithani, V. Bakatselou, C. N. TenHoor, and J. B. Dressman. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharm Res. 13:163–167 (1996). doi:10.1023/A:1016062224568.
H. Mizuuchi, V. Jaitely, S. Murdan, and A. T. Florence. Room temperature ionic liquids and their mixtures: potential pharmaceutical solvents. Eur J Pharm Sci. 33:326–331 (2008). doi:10.1016/j.ejps.2008.01.002.
V. Bakatselou, R. C. Oppenheim, and J. B. Dressman. Solubilization and wetting effects of bile salts on the dissolution of steroids. Pharm Res. 8:1461–1469 (1991). doi:10.1023/A:1015877929381.
D. Ilardia-Arana, H. G. Kristensen, and A. Müllertz. Biorelevant dissolution media: aggregation of amphiphiles and solubility of estradiol. J Pharm Sci. 95:248–255 (2006). doi:10.1002/jps.20494.
N. H. Zangenberg, A. Müllertz, H. G. Kristensen, and L. Hovgaard. A dynamic in vitro lipolysis model. II: evaluation of the model. Eur J Pharm Sci. 14:237–244 (2001). doi:10.1016/S0928-0987(01)00182-8.
M. Grove, G. P. Pedersen, J. L. Nielsen, and A. Müllertz. Bioavailability of seocalcitol I: relating solubility in biorelevant media with oral bioavailability in rats—effect of medium and long chain triglycerides. J Pharm Sci. 94:1830–1838 (2005). doi:10.1002/jps.20403.
A. M. Kaukonen, B. J. Boyd, C. J. H. Porter, and W. N. Charman. Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharm Res. 21:245–253 (2004). doi:10.1023/B:PHAM.0000016282.77887.1f.
J. Ø. Christensen, K. Schultz, B. Mollgaard, H. G. Kristensen, and A. Müllertz. Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium- and long-chain triacylglycerols. Eur J Pharm Sci. 23:287–296 (2004). doi:10.1016/j.ejps.2004.08.003.
P. B. Nielsen, A. Müllertz, T. Norling, and H. G. Kristensen. The effect of alpha-tocopherol on the in vitro solubilisation of lipophilic drugs. Int J Pharm. 222:217–224 (2001). doi:10.1016/S0378-5173(01)00701-3.
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). doi:10.1002/jps.10329.
Acknowledgements
This research was funded by a Ph.D. grant of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen), as well as from grants from the ‘Fonds voor Wetenschappelijk Onderzoek’ (FWO), Flanders and from the ‘Onderzoeksfonds’ of the K.U.Leuven, Belgium. We also wish to thank Rita Vos and Toon De Greef (Gastroenterology, University Hospitals Leuven, Belgium) for their assistance during the in vivo studies. Dr. Eric Deconinck is acknowledged for his expertise and assistance in performing the statistical analyses. D. Psachoulias was partly supported by the European Commission Program Socrates, Erasmus—Action 2.2.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Clarysse, S., Psachoulias, D., Brouwers, J. et al. Postprandial Changes in Solubilizing Capacity of Human Intestinal Fluids for BCS Class II Drugs. Pharm Res 26, 1456–1466 (2009). https://doi.org/10.1007/s11095-009-9857-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-009-9857-7