Permeability of lipophilic compounds in drug discovery using in-vitro human absorption model, Caco-2

Highly lipophilic compounds are often encountered in the early stages of drug discovery. The apparent permeability (Papp) of these compounds in Caco-2 cell could be underestimated because of considerable retention by the Caco-2 monolayer and non-specific binding to transwell surface. We have utilize...

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Bibliographic Details
Published in:International journal of pharmaceutics 2001-07, Vol.222 (1), p.77-89
Main Authors: Krishna, Gopal, Chen, Kwang-jong, Lin, Chin-chung, Nomeir, Amin A
Format: Article
Language:English
Subjects:
Biological and medical sciences
Bovine serum albumin
Caco-2
Caco-2 Cells - metabolism
Chemistry, Pharmaceutical
General pharmacology
Humans
Lipophilic compounds
Mannitol - pharmacokinetics
Medical sciences
Molecular Weight
Non-specific binding
Oral absorption
Permeability
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Progesterone - pharmacokinetics
Propranolol - pharmacokinetics
Structure-Activity Relationship
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Summary:Highly lipophilic compounds are often encountered in the early stages of drug discovery. The apparent permeability (Papp) of these compounds in Caco-2 cell could be underestimated because of considerable retention by the Caco-2 monolayer and non-specific binding to transwell surface. We have utilized a general approach for the determination of permeability of these compounds, which includes the addition of 1–5% DMSO in the apical (AP) and 4% bovine serum albumin (BSA) in the basolateral (BA) side. Two highly lipophilic and highly protein bound Schering compounds, SCH-A and SCH-B, exhibited poor recovery and low Papp in the conventional Caco-2 system that included 1% DMSO in the AP and BA sides. In contrast, both compounds were well absorbed in cynomolgus monkeys. Inclusion of BSA (up to 4%) in the BA side provided necessary absorptive driving force similar to in vivo sink conditions improving both recovery and Papp of these compounds as well as progesterone, a model highly lipophilic and highly protein bound compound. Whereas, the recovery and Papp of mannitol (high recovery, low permeability) and propranolol (high recovery, high permeability) remained unaffected. The presence of 4% BSA increased Papp of SCH-A, SCH-B, and progesterone by five-, four-, and three-fold, respectively. We also compared this approach with a second, based on the disappearance of the compound from the AP side, which resulted in a reasonable estimate of the permeability (23.3×10 −6 cm/s) for SCH-A. The results demonstrated that the reliable estimates of permeability of highly lipophilic compounds that are subjected to considerable retention by the cell monolayer and exhibit non-specific binding are obtained by the addition of BSA to the BA side.
ISSN:0378-5173
1873-3476
DOI:10.1016/S0378-5173(01)00698-6