• Intratracheal aerosolization of 99m TcTc-sestamibi • Dynamic planar gamma scintigraphy to assess pulmonary pharmacokinetics • Use of transporter knockout mice and transporter inhibition • 99m TcTc-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 TcTc-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 TcTc-sestamibi for imaging transporter activity in the lungs. We measured pulmonary elimination kinetics by dynamic planar gamma scintigraphy following intratracheal aerosolization of 99m TcTc-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 TcTc-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 TcTc-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 TcTc-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.
Mairinger et al. (Sun,) studied this question.