Development of Cassette PAMPA for Permeability Screening

Development of Cassette PAMPA for Permeability Screening

The parallel artificial membrane permeability assay (PAMPA) is widely used in early-stage drug discovery to discriminate compounds by intestinal permeability. The purpose of the current study was to establish a cassette (n-in-1) PAMPA to enable permeability screening of lipophilic compounds. A doubl...

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Bibliographic Details
Published in:Biological and Pharmaceutical Bulletin Vol. 40; no. 4; pp. 419 - 424
Main Authors: Mun Hwan Oha, Hye Jin Leea, Sang Hyun Joa, Bernie Byunghoon Parka, Sae-Bom Parka, Eun-yeong Kima, Yuanyuan Zhoua, Young Ho Jeona, Kiho Leea, b
Format: Journal Article
Language:Japanese
Published: Pharmaceutical Society of Japan 01-04-2017
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Summary:The parallel artificial membrane permeability assay (PAMPA) is widely used in early-stage drug discovery to discriminate compounds by intestinal permeability. The purpose of the current study was to establish a cassette (n-in-1) PAMPA to enable permeability screening of lipophilic compounds. A double-sink PAMPA consisting of a pH gradient (i.e., pH 6.5 and 7.4 for the donor and receiver compartments, respectively) and a lipophilic sink (i.e., a surfactant in the receiver solution) was utilized with cassette incubation of 10 reference compounds. Sample analysis was conducted using selected reaction monitoring (SRM) with a triple quadrupole LC-MS/MS system. Correlation between PAMPA permeability and human intestinal absorption (HIA) of the reference compounds yielded two false negatives, namely propranolol (PPN) and verapamil (VER) ; these two compounds showed a substantially lower recovery (ca. 10%) than other reference compounds (>69%). This cassette PAMPA was repeated subsequently with polysorbate 80 added to the donor compartments, which resulted in a significant increase in both the recovery and the permeability of the false negatives. Accordingly, the permeability class of all reference compounds could be unambiguously differentiated using this cassette PAMPA. Also, a strong linear correlation (r=0.9845) was observed between the cassette and discrete permeability of all reference compounds.
ISSN:0918-6158