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The AAPS Journal

, Volume 10, Issue 4, pp 577–586 | Cite as

P-gp Inhibition Potential in Cell-Based Models: Which “Calculation” Method is the Most Accurate?

  • Praveen V. Balimane
  • Anthony Marino
  • Saeho Chong
Research Article

Abstract

The objective was to directly compare the four different “calculation” methods of assessing P-gp inhibition potential using experimental data obtained from ~60 structurally diverse internal research and marketed compounds. Bidirectional studies for digoxin (probe for P-gp substrate) were performed with and without test compounds (at 10 μM). Four different calculation methods were applied to the same dataset (raw bidirectional permeability values) to obtain the “percent inhibition of P-gp” for these compounds using the different methods. Significantly different inhibition potential was obtained with the “exact” same experimental dataset depending on the calculation method used. Subsequently, entirely different conclusions regarding the “inhibition potential” of test compound was reached due to the different calculation methods. Based on the direct comparison of these methods, method no. 3 (i.e., inhibition of B to A permeability of digoxin) is recommended as the calculation method ideal during screening stages due to its high throughput amenability. The methodology is capable of rapidly screening compounds with adequate reliability for early stage drug discovery. Method no. 3 provides an abridged version of a bidirectional study that is fully capable of identifying all non-inhibitors (0–20%), moderate inhibitors (20–60%), and potent inhibitors (>60%) and demonstrates high correlation with method no. 1 (inhibition based on both A to B and B to A permeability of digoxin). Nevertheless, method no. 1 might be appropriate for more detailed mechanistic studies required in late stage discovery and development.

Key words

drug–drug interactions efflux ratio in vitro models P-gp inhibition permeability 

Abbreviations

A to B

Apical to basolateral

ADME

Absorption, distribution, metabolism, elimination

B to A

Basolateral to apical

BCRP

Breast cancer resistance protein

CNS

Central nervous system

FDA

Food and drug administration

HBSS

Hank’s balanced salt solution

HEPES

N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid

LSC

Liquid scintillation counting

MDCK

Mardin Darby canine kidney

MRP

Multi-drug resistance protein

PAMPA

Parallel artificial membrane permeability assay

P-gp

P-glycoprotein

Pc

Permeability coefficient

TEER

Transepithelial electrical resistance

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Copyright information

© American Association of Pharmaceutical Scientists 2008

Authors and Affiliations

  • Praveen V. Balimane
    • 1
  • Anthony Marino
    • 1
  • Saeho Chong
    • 1
  1. 1.Metabolism and PharmacokineticsBristol-Myers SquibbPrincetonUSA

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