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Advantages and disadvantages of using bovine serum albumin and/or Cremophor EL as extracellular additives during transport studies of lipophilic compounds across Caco-2 monolayers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2007 (English)In: Journal of drug delivery science and technology, ISSN 1773-2247, Vol. 17, no 4, 259-266 p.Article in journal (Refereed) Published
Abstract [en]

The effects of Cremophor EL (CEL) and bovine serum albumin (BSA) on the active and passive permeation of BCS class II compounds (felodipine, asimadoline) were studied across Caco-2 cells. The effect of BSA on either or both sides of the monolayers, apically applied CEL in the presence ofbasolateral BSA and the effect ofaddition of CEL on P-gp by the use ofquinidine were investigated. Presence of 4% BSA improved sink conditions and recovery from 60 to 95% for both felodipine and asimadoline. Efflux ratios obtained under comparable sink conditions, indicated that felodipine was transported by passive diffusion, while quinidine and asimadoline were transported actively. CEL decreased the transport rate for felodipine and asimadoline in the absorptive direction and increased in the secretory direction at different CEL concentrations, most likely due to the incorporation of drug into micelles. Our results indicate that inclusion of BSA is generally sufficient to increase the recovery for lipophilic BCS class II compounds. The overall effect of CEL on the permeability of a drug is compound specific and, therefore, less predictable and cannot be recommended.

Place, publisher, year, edition, pages
2007. Vol. 17, no 4, 259-266 p.
Keyword [en]
Physicochemical properties, Pharmacokinetics, Vertebrata, Mammalia, Ungulata, Artiodactyla, Pharmaceutical technology, Solubility, Castor oil, MDR-1 gene, Absorption, Drug, Lipophilic compound, Transport, Additive, Serum albumin, Ox, Animal
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93112ISI: 000250032200005OAI: oai:DiVA.org:uu-93112DiVA: diva2:166490
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2011-01-22Bibliographically approved
In thesis
1. Refined in vitro Models for Prediction of Intestinal Drug Transport: Role of pH and Extracellular Additives in the Caco-2 Cell Model
Open this publication in new window or tab >>Refined in vitro Models for Prediction of Intestinal Drug Transport: Role of pH and Extracellular Additives in the Caco-2 Cell Model
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Drug transport across the intestinal epithelium is roughly predicted from permeability values obtained from Caco-2 cell monolayers. This thesis examines the important role of pH and extracellular additives for increasing the reliability and predictivity of the in vitro screening system, Caco-2.

It was shown that the passive transport of ionizable compounds may be biased by a false efflux or uptake component, when applying a physiological pH-gradient across the membrane. pH also affected the amount of compound available at the transporter-binding site. Therefore, pH dependence should be considered in studies of such compounds and of drug-drug interactions involving efflux transporters. It was also shown that proton-dependent apical uptake or basolateral efflux should be studied both with and without a pH gradient over the whole monolayers.

The two extracellular additives, bovine serum albumin (BSA) and the solubilizing agent, Cremophor® EL, also influenced Caco-2 permeabilities. BSA applied to the receiver side increases, and to the donor side decreases drug permeation according to the drug’s protein binding capacity. Thus, the absorptive transport for both passive and active compounds is favoured, giving a physiologically sound improvement of the Caco-2 cell model. Inclusion of BSA increased both the predictivity and quality of permeability studies, particularly of highly lipophilic, BCS class II compounds. Passive and active transport processes could also be distinguished after accounting for unbound concentrations. The overall effect of Cremophor® EL on the permeability to a drug was compound-specific and probably dependent on micellar incorporation. Cremophor® EL can therefore not be recommended.

Neither pH nor BSA affect the functionality of transporters such as P-glycoprotein. However, efflux ratios of ionizable or protein bound drugs are altered in the presence of a pH-gradient or BSA, indicating that an experimental system without protein or pH gradient can over- or underestimate active and passive efflux in drug transport.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 83 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 14
Keyword
Pharmacy, Caco-2 cells, membrane permeability, drug permeation, drug efflux ratios, drug uptake ratios, Cremophor EL, bovine serum albumin, pH-dependent permeability, drug transport, FARMACI
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-5814 (URN)91-554-6262-6 (ISBN)
Public defence
2005-06-02, B22, Uppsala Biomediciniska centrum, Uppsala, 13:15
Opponent
Supervisors
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2011-09-19Bibliographically approved

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