ADMET and DMPK, Vol. 3. No. 1., 2015.
Original scientific paper
https://doi.org/10.5599/admet.3.1.169
Adaptation of a human gut epithelial model in relation to the assessment of clinical pharmacokinetic parameters for selected tyrosine kinase inhibitors
Richard J Honeywel
; De pt. of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
Christien Fatmawati
; De pt. of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
Marita Buddha
; De pt. of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
Sarina Hitzerd
; De pt. of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
Ietje Kathman
; De pt. of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
Godefridus J. Peters
orcid.org/0000-0002-5447-2877
; De pt. of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
Abstract
The absorption, efflux and transport properties of two of the most commonly used tyrosine kinase inhibitors (TKIs), Erlotinib (E) and Gefitinib (G) were investigated using an adapted workable methodology of a 3-day Caco-2 cell monolayer transwell system, a standard model to test drug permeability and uptake of orally administered compounds. Monolayer integrity was tested using trans-epithelial electrical resistance (TEER) measurements, while drug concentrations were determined with a validated LC-MS/ MS technique. Addition of 5 % bovine serum albumin (BSA) maintained drug concentrations at 20 µM through the avoidance of chelate formation, (nevertheless, a reduced accumulative mass transport of the protein bound drug was observed). Investigation with Ko143 (a specific blocker of ABCG2) or NaN3 (a metabolic inhibitor) indicated an interplay between active transport and passive diffusion for gefitinib, while active transport proved to be absent for erlotinib (p < 0.05). The mechanism indicates that ABCG2 is partially involved with accumulation of gefitinib in the cell. This adapted methodology is well suited for absorption, efflux and transport studies and may be extended to investigate the dominant mechanism involved in the transport of TKIs.
Keywords
Tyrosine kinase inhibitors; Caco-2 transwell; gut epithelial; gutmodel; drug absorption
Hrčak ID:
137564
URI
Publication date:
31.3.2015.
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