Permeability screening

Irvine JD, Takahashi L, Lockhart K, Cheong J, Tolan JW, Selick HE, et al. MDCK (Madin-Darby canine kidney) cells a tool for membrane permeability screening. J Pharm Sci 1999 88 28-33. 

Permeability is a property closely tied to the environment of the epithelial cell surface. There is little point in measuring permeability at pH 1.7, if the microclimate barrier has pH >5 and <8, averaging 6. An in vitro permeability screen based on donor pH 5.0-7.4 and acceptor pH 7.4 seems about right. It will be useful to correct the data for the unstirred water layer effect, using computational methods. 

Gumbleton, M. and K. L. Audus. Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier, J. Pharm. Sci. 2001, 90, 1681-1698... 

Use of Caco-2 Cells in Drug Discovery 9.3.1 High-Throughput Permeability Screening... 

Recently, Caco-2 permeability screening has been optimized to accommodate the increasing demand for permeability assessment. Analytical methods like HPLC coupled with UV, evaporative light scattering detection (ELSD), or fluorescence detection were used traditionally... 

Another in vitro method for permeability screening was parallel artificial membrane permeation assay (PAMPA) initially reported by Kansy. In a PAMPA permeability screen, the Caco-2 cell mono-layer membrane is replaced by an artificially generated membrane. Versions of different artificial membranes that lack active transporter systems and pores have been developed to mimic the in vivo transcellular intestinal epithelial cell barrier. Therefore, the PAMPA screen only measures the intrinsic... 

LC/MS/MS techniques with selective and sensitive detection methods make it possible to quantitatively analyze samples from Caco-2 cell and PAMPA buffer matrices. A high-throughput permeability screen with robust LC/MS technology can quickly generate information about structure-permeability relationships that are extremely valuable in the lead optimization phase for the selection of pre-clinical candidates with favorable oral bioavailability properties. 

Matsson, P., Bergstroem, C.A.S., Nagahara, N., Tavelin, S., Norinder, U. and Artursson, P. (2005) Exploring the role of different drug transport routes in permeability screening. Journal of Medicinal Chemistry, 48, 604—613. 

The use of in vitro cell culture models for mechanistic studies and as permeability screens for the blood-brain barrier in the pharmaceutical Industry-Background and current status in the drug discovery process. Vascular Pharmacology, 38, 355-364. 

---