Journal of pharmacological and toxicological methods, 2014-09, Vol.70 (2), p.188-194
2014
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- Autor(en) / Beteiligte
- Titel
- Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations
- Ist Teil von
- Journal of pharmacological and toxicological methods, 2014-09, Vol.70 (2), p.188-194
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2014
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- Malaria is a major health concern and affects over 300million people a year. Accordingly, there is an urgent need for new efficacious anti-malarial drugs. A major challenge in developing new anti-malarial drugs is to design active molecules that have preferable drug-like characteristics. These “drug-like” characteristics include physiochemical properties that affect drug absorption, distribution, metabolism, and excretion (ADME). Compounds with poor ADME profiles will likely fail in vivo due to poor pharmacokinetics and/or other drug delivery related issues. There have been numerous assays developed in order to pre-screen compounds that would likely fail in further development due to poor absorption properties including PAMPA, Caco-2, and MDCK permeability assays. The use of cell-based permeability assays such as Caco-2 and MDCK serve as surrogate indicators of drug absorption and transport, with the two approaches often used interchangeably. We sought to evaluate both approaches in support of anti-malarial drug development. Accordingly, a comparison of both assays was conducted utilizing apparent permeability coefficient (Papp) values determined from liquid chromatography/tandem mass spectrometry (LC-MS) analyses. Both Caco-2 and MDCK permeability assays produced similar Papp results for potential anti-malarial compounds with low and medium permeability. Differences were observed for compounds with high permeability and compounds that were P-gp substrates. Additionally, the utility of MDCK-MDR1 permeability measurements was demonstrated in probing the role of P-glycoprotein transport in Primaquine–Chloroquine drug–drug interactions in comparison with in vivo pharmacokinetic changes. This study provides an in-depth comparison of the Caco-2 and MDCK-MDR1 cell based permeability assays and illustrates the utility of cell-based permeability assays in anti-malarial drug screening/development in regard to understanding transporter mediated changes in drug absorption/distribution.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1056-8719eISSN: 1873-488XDOI: 10.1016/j.vascn.2014.08.002Titel-ID: cdi_proquest_miscellaneous_1562441249
- Format
- –
- Schlagworte
- Absorption, Physiological - drug effects, Animals, Anti-malarial drug development, Antimalarials - chemistry, Antimalarials - metabolism, Antimalarials - pharmacokinetics, Caco-2, Caco-2 Cells, Cells, Cultured, Chromatography, Liquid, Dogs, Drug Delivery Systems, Drug Design, Drug Evaluation, Preclinical - methods, Humans, Madin Darby Canine Kidney Cells, Male, MDCK, MDCK-MDR1, Mice, Mice, Inbred C3H, Permeability, Permeability - drug effects, Primaquine–Chloroquine interaction, Tandem Mass Spectrometry