Impact of P-gp and BCRP on pulmonary drug disposition assessed by PET imaging in rats.

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters which are expressed in the apical (i.e. airway lumen-facing) membranes of lung epithelial cells. To assess the influence of P-gp and BCRP on the pulmonary disposition of inhaled drugs, we performed positron emission tomography (PET) imaging in rats after intratracheal aerosolization of two model P-gp/BCRP substrate radiotracers (i.e. [C]erlotinib and [C]tariquidar). We studied rat groups in which both transporters were active (i.e. wild-type rats), either of the two transporters was inactive (Abcb1a/b and Abcg2 rats) or both transporters were inactive (Abcg2 rats in which pulmonary P-gp activity was inhibited by treatment with unlabeled tariquidar). PET-measured lung distribution data were compared with brain-to-plasma radioactivity concentration ratios measured in a gamma counter at the end of the PET scan. For [C]erlotinib, lung exposure (AUC) was moderately but not significantly increased in Abcb1a/b rats (1.6-fold) and Abcg2 rats (1.5-fold), and markedly (3.6-fold, p < 0.0001) increased in tariquidar-treated Abcg2 rats, compared to wild-type rats. Similarly, the brain uptake of [C]erlotinib was substantially (4.5-fold, p < 0.0001) increased when both P-gp and BCRP activities were impaired. For [C]tariquidar, differences in AUC between groups pointed into a similar direction as for [C]erlotinib, but were less pronounced and lacked statistical significance. Our study demonstrates functional P-gp and BCRP activity in vivo in the lungs and further suggests functional redundancy between P-gp and BCRP in limiting the pulmonary uptake of a model P-gp/BCRP substrate, analogous to the blood-brain barrier. Our results suggest that pulmonary efflux transporters are important for the efficacy and safety of inhaled drugs and that their modulation may be exploited in order to improve the pharmacokinetic and pharmacodynamic performance of pulmonary delivered drugs.