10.1021/mp300472y.s001
Emma Portnoy
Emma
Portnoy
Marina Gurina
Marina
Gurina
Shlomo Magdassi
Shlomo
Magdassi
Sara Eyal
Sara
Eyal
Evaluation of the Near
Infrared Compound Indocyanine
Green as a Probe Substrate of P‑Glycoprotein
American Chemical Society
2012
ICG accumulation
EC 50 values
BCRP
breast cancer resistance protein
vivo imaging
MDR
efflux
probe substrate
control MDCK cells
2012-12-03 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Evaluation_of_the_Near_Infrared_Compound_Indocyanine_Green_as_a_Probe_Substrate_of_P_Glycoprotein/2464735
The efflux transporter P-glycoprotein (P-gp) affects
the pharmacokinetics
of many drugs. Currently used methods for characterization of P-gp’s
functional activity <i>in vivo</i> involve the use of radiolabeled
substrates, are costly, and are technically demanding. Our objective
was to evaluate whether the FDA-approved near-infrared compound indocyanine
green (ICG) can be used as a probe substrate of P-gp. We also characterized
the interaction of ICG with another efflux transporter, the breast
cancer resistance protein (BCRP). We evaluated ICG accumulation and
transport in MDCK cells overexpressing P-gp or BCRP (MDCK-MDR1 and
MDCK-BCRP, respectively) compared to control MDCK cells, in the presence
or the absence of transporter inhibitors. <i>In vivo</i> imaging of ICG biodistribution in mice was conducted over 3.5 h
using valspodar as the P-gp inhibitor. The EC<sub>50</sub> values
for ICG accumulation in control MDCK and MDCK-MDR1 cells were 9.0
× 10<sup>–6</sup> ± 5.7 × 10<sup>–7</sup> M and 1.5 × 10<sup>–5</sup> ± 1.1 × 10<sup>–6</sup> M, respectively. The efflux ratio for ICG in MDCK-MDR1
cells was 6.8-fold greater than in control cells. P-gp inhibition
attenuated ICG efflux from MDR1-MDCK cells, and their effects in those
cells were greater than in control MDCK cells. In contrast, BCRP level
of expression or pharmacological inhibition did not significantly
affect ICG cellular accumulation. <i>In vivo</i> imaging
indicated enhanced cerebral ICG distribution with valspodar (brain
– foot area under the concentration–time curves of 3.0
× 10<sup>10</sup>, 5.6 × 10<sup>10</sup> and 3.7 ×
10<sup>10</sup> h·[p/s/sr]/μW in valspodar-treated mice
vs 9.0 × 10<sup>9</sup> and 5.3 × 10<sup>9</sup> h·[p/s/sr]/μW
in controls). The findings from this pilot study suggest that near-infrared
imaging using ICG as the probe substrate should be further characterized
as a methodology for <i>in vivo</i> evaluation of P-gp activity.