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A template model for studying anticancer drug efflux transporter inhibitors in vitro
Author(s) -
Sostelly Alexandre,
Payen Léa,
Guitton Jérôme,
Pietro Attilio Di,
Falson Pierre,
Honorat Mylène,
Valdameri Glaucio,
Geze Annabelle,
Boumendjel Ahcène,
Freyer Gilles,
Tod Michel
Publication year - 2013
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2012.01054.x
Subject(s) - efflux , abcg2 , transporter , pharmacology , in vitro , chemistry , intracellular , in vivo , metabolite , biophysics , atp binding cassette transporter , biochemistry , biology , microbiology and biotechnology , gene
Efflux transporters play an important role in drug absorption and also in multidrug resistance. ABCG 2 ( BCRP ) is an efflux transporter conferring cross‐resistance to mitoxantrone ( M it), irinotecan ( CPT 11), and its active metabolite SN 38. MBLI 87, a new ABCG 2 inhibitor has proven its efficacy against ABCG 2‐mediated efflux in vitro and in vivo. This work aimed at modeling and quantifying the cellular interaction between MBLI 87 and different substrates using a mechanistic template model. An in vitro competition experiment study was carried out with HEK 293 cells overexpressing ABCG 2 exposed to fixed concentrations of substrates ( M it, CPT 11, SN 38) and to MBLI 87 at several concentration levels. A nonlinear mixed‐effects transport inhibition model was developed to fit intracellular drug concentrations. In this model, drugs cross the cell membrane through passive diffusion, active drug efflux is ABCG 2 mediated, interaction between substrates and inhibitor occurs within the transporter. The interaction was found to be noncompetitive. The MBLI 87 K i was estimated to 141 n m for M it, 289 n m for CPT 11, and 1160 n m for SN 38. The ratio of intrinsic transport clearance divided by diffusion clearance was estimated to 2.5 for Mit, 1.01 for CPT 11, and 5.4 for SN 38. The maximal increase in the intracellular substrate concentration that is possible to achieve by inhibition of the transporter was estimated to 1.5 for M it, 0.1 for CPT 11, and 4.4 for SN 38. This mechanistic template model describes both drug accumulation and cellular transport, and the mixed‐effects approach allows an estimation of intra‐ and interassay variability. This model is of great interest to study cytotoxic cellular pharmacokinetics.