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In situ artificial membrane permeation assay under hydrodynamic control: Permeability-ph profiles of warfarin and verapamil
Velicky M.1; Bradley D.F.1; Tam K.Y.2; Dryfe R.A.W.1
2010-08-01
Source PublicationPharmaceutical Research
ISSN07248741 1573904X
Volume27Issue:8Pages:1644-1658
Abstract

Purpose: To investigate the permeation of two ionisable drug molecules, warfarin and verapamil, across artificial membranes. For the first time since the introduction of the parallel artificial membrane permeation assay (PAMPA) in 1998, in situ permeation-time profiles of drug molecules are studied. Methods: The method employs a rotating-diffusion cell where the donor and acceptor compartments are separated by a lipid-impregnated artificial membrane. The permeation of the solute is investigated under well-defined hydrodynamic conditions with control over the unstirred water layer. The flux of the permeating molecule is analysed in situ using UV spectrophotometry. Results: In situ permeation-time profiles are obtained under hydrodynamic control and used to determine permeability coefficients. An advanced analytical transport model is derived to account for the membrane retention, two-way flux and pH gradient between the two compartments. Moreover, a numerical permeation model was developed to rationalise the time-dependent permeation profiles. The membrane permeability, intrinsic permeability and unstirred water permeability coefficients of two drug molecules are obtained from two independent methods, hydrodynamic extrapolation and pH profiling, and the results are compared. Conclusions: Both warfarin and verapamil exhibit high permeability values, which is consistent with the high fraction absorbed in human. Our results demonstrate that a considerable lag-time, varying with the solute lipophilicity and stirring rate, exists in membrane permeation and leads to incorrect compound ranking if it is not treated properly. Comparison of the permeability data as a function of pH and stirring rate suggests that some transport of the ionized molecules occurs, most likely via ion-pairing. © 2010 Springer Science+Business Media, LLC.

KeywordHydrodynamic Control In Situ Permeation Pampa Permeability Unstirred Water Layer
DOI10.1007/s11095-010-0150-6
URLView the original
Indexed BySCI
Language英语
WOS Research AreaChemistry ; Pharmacology & Pharmacy
WOS SubjectChemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS IDWOS:000279506100015
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Cited Times [WOS]:26   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.University of Manchester
2.AstraZeneca
Recommended Citation
GB/T 7714
Velicky M.,Bradley D.F.,Tam K.Y.,et al. In situ artificial membrane permeation assay under hydrodynamic control: Permeability-ph profiles of warfarin and verapamil[J]. Pharmaceutical Research,2010,27(8):1644-1658.
APA Velicky M.,Bradley D.F.,Tam K.Y.,&Dryfe R.A.W..(2010).In situ artificial membrane permeation assay under hydrodynamic control: Permeability-ph profiles of warfarin and verapamil.Pharmaceutical Research,27(8),1644-1658.
MLA Velicky M.,et al."In situ artificial membrane permeation assay under hydrodynamic control: Permeability-ph profiles of warfarin and verapamil".Pharmaceutical Research 27.8(2010):1644-1658.
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