Imaging pulmonary P-glycoprotein activity with aerosolized [99mTc]Tc-sestamibi in mice

Résumé fourni par la source

• Intratracheal aerosolization of [ 99m Tc]Tc-sestamibi • Dynamic planar gamma scintigraphy to assess pulmonary pharmacokinetics • Use of transporter knockout mice and transporter inhibition • [ 99m Tc]Tc-sestamibi as a probe to measure pulmonary P-gp activity • Potential utility for studying transporter-mediated drug-drug interactions in the lung Adenosine triphosphate-binding cassette (ABC) transporters are expressed throughout the lung epithelium, where they may influence the pulmonary disposition of inhaled therapeutics and contribute to transporter-mediated drug-drug interactions. Imaging approaches using radiolabeled transporter-specific probe substrates potentially offer a means to assess drug-transporter interactions directly in the lung. [ 99m Tc]Tc-sestamibi, a widely used myocardial perfusion tracer, is a known substrate of P-glycoprotein (P-gp/ABCB1) and multidrug resistance-associated protein 1 (MRP1/ABCC1). Here, we evaluated the suitability of [ 99m Tc]Tc-sestamibi for imaging transporter activity in the lungs. We measured pulmonary elimination kinetics by dynamic planar gamma scintigraphy following intratracheal aerosolization of [ 99m Tc]Tc-sestamibi in wild-type and MRP1-deficient ( hABCC1 (−/−) ) mice, with and without co-administration of the P-gp inhibitor tariquidar. P-gp inhibition significantly reduced the pulmonary elimination rate constant ( k E ) of [ 99m Tc]Tc-sestamibi (1.14 ± 0.32 h −1 in wild-type mice versus 0.56 ± 0.36 h −1 in tariquidar-treated wild-type mice; P = 0.0056). In contrast, MRP1 deficiency did not alter pulmonary elimination of [ 99m Tc]Tc-sestamibi (0.93 ± 0.23 h −1 ), and combined MRP1 deficiency with P-gp inhibition (0.61 ± 0.24 h −1 ) produced no additional effect beyond P-gp inhibition alone. These findings indicate that pulmonary disposition of [ 99m Tc]Tc-sestamibi is primarily governed by P-gp, with minimal contribution from MRP1 in mice, supporting its potential use as an imaging probe of pulmonary P-gp activity. Nevertheless, given possible species differences in transporter abundance, cellular localization, or function, clinical studies are required to evaluate the translatability of these results to humans.

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