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A general approach to the apparent permeability index

Palumbo, Pasquale; Picchini, Umberto LU ; Beck, Benoit; van Gelder, Jan; Delbar, Nathalie and De Gaetano, Andrea (2008) In Journal of Pharmacokinetics and Pharmacodynamics 35(2). p.235-248
Abstract
The apparent permeability index is widely used as part of a general screening process to study drug absorption, and is routinely obtained from in vitro or ex vivo experiments. A classical example, widely used in the pharmaceutical industry, is the in vitro Caco-2 cell culture model. The index is defined as the initial flux of compound through the membrane (normalized by membrane surface area and donor concentration) and is typically computed by adapting a straight line to the initial portion of the recorded amounts in the receiver compartment, possibly disregarding the first few points when lagging of the transfer process through the membrane is evident. Modelling the transfer process via a two-compartmental system yields an immediate... (More)
The apparent permeability index is widely used as part of a general screening process to study drug absorption, and is routinely obtained from in vitro or ex vivo experiments. A classical example, widely used in the pharmaceutical industry, is the in vitro Caco-2 cell culture model. The index is defined as the initial flux of compound through the membrane (normalized by membrane surface area and donor concentration) and is typically computed by adapting a straight line to the initial portion of the recorded amounts in the receiver compartment, possibly disregarding the first few points when lagging of the transfer process through the membrane is evident. Modelling the transfer process via a two-compartmental system yields an immediate analogue of the common Papp as the initial slope of the receiver quantity, but the two-compartment model often does not match observations well. A three-compartment model, describing the cellular layer as well as donor and receiver compartments, typically better represents the kinetics, but has the disadvantage of always having zero initial flow rate to the receiver compartment: in these circumstances the direct analogue of the Papp index is not informative since it is always zero. In the present work an alternative definition of an apparent permeability index is proposed for three-compartment models, and is shown to reduce to the classical formulation as the cellular layer's volume tends towards zero. This new index characterizes the intrinsic permeability of the membrane to the compound under investigation, can be directly computed in a completely observer-independent fashion, and reduces to the usual Papp when the linear two-compartment representation is sufficient to accurately describe compound kinetics. (Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Drug discovery, Papp, Permeability index, Mathematical models, Caco-2
in
Journal of Pharmacokinetics and Pharmacodynamics
volume
35
issue
2
pages
235 - 248
publisher
Springer
external identifiers
  • scopus:43949112271
ISSN
1567-567X
DOI
10.1007/s10928-008-9086-4
language
English
LU publication?
no
id
8f338fbb-22ce-4cc8-b905-d766b5100f6d (old id 4216000)
date added to LUP
2014-01-13 14:12:12
date last changed
2017-09-17 05:22:16
@article{8f338fbb-22ce-4cc8-b905-d766b5100f6d,
  abstract     = {The apparent permeability index is widely used as part of a general screening process to study drug absorption, and is routinely obtained from in vitro or ex vivo experiments. A classical example, widely used in the pharmaceutical industry, is the in vitro Caco-2 cell culture model. The index is defined as the initial flux of compound through the membrane (normalized by membrane surface area and donor concentration) and is typically computed by adapting a straight line to the initial portion of the recorded amounts in the receiver compartment, possibly disregarding the first few points when lagging of the transfer process through the membrane is evident. Modelling the transfer process via a two-compartmental system yields an immediate analogue of the common Papp as the initial slope of the receiver quantity, but the two-compartment model often does not match observations well. A three-compartment model, describing the cellular layer as well as donor and receiver compartments, typically better represents the kinetics, but has the disadvantage of always having zero initial flow rate to the receiver compartment: in these circumstances the direct analogue of the Papp index is not informative since it is always zero. In the present work an alternative definition of an apparent permeability index is proposed for three-compartment models, and is shown to reduce to the classical formulation as the cellular layer's volume tends towards zero. This new index characterizes the intrinsic permeability of the membrane to the compound under investigation, can be directly computed in a completely observer-independent fashion, and reduces to the usual Papp when the linear two-compartment representation is sufficient to accurately describe compound kinetics.},
  author       = {Palumbo, Pasquale and Picchini, Umberto and Beck, Benoit and van Gelder, Jan and Delbar, Nathalie and De Gaetano, Andrea},
  issn         = {1567-567X},
  keyword      = {Drug discovery,Papp,Permeability index,Mathematical models,Caco-2},
  language     = {eng},
  number       = {2},
  pages        = {235--248},
  publisher    = {Springer},
  series       = {Journal of Pharmacokinetics and Pharmacodynamics},
  title        = {A general approach to the apparent permeability index},
  url          = {http://dx.doi.org/10.1007/s10928-008-9086-4},
  volume       = {35},
  year         = {2008},
}