Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
J Control Release. 2022 Sep;349:109-117. doi: 10.1016/j.jconrel.2022.06.065. Epub 2022 Jul 8.
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.
P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）是两种外排转运蛋白，它们在肺上皮细胞的顶膜（即气道腔面向）表达。为了评估 P-gp 和 BCRP 对吸入药物肺部处置的影响，我们通过正电子发射断层扫描（PET）在气管内雾化两种模型 P-gp/BCRP 底物放射性示踪剂（即 [C]厄洛替尼和 [C]塔里奎达后，在大鼠中进行了成像。我们研究了两种转运蛋白均活跃的大鼠组（即野生型大鼠）、两种转运蛋白均不活跃的大鼠组（Abcb1a/b 和 Abcg2 大鼠）或两种转运蛋白均不活跃的大鼠组（Abcg2 大鼠，其肺 P-gp 活性被未标记的塔里奎达抑制）。将 PET 测量的肺部分布数据与在 PET 扫描结束时在伽马计数器中测量的脑-血浆放射性浓度比进行比较。对于 [C]厄洛替尼，与野生型大鼠相比，Abcb1a/b 大鼠（1.6 倍）和 Abcg2 大鼠（1.5 倍）中肺暴露（AUC）适度但无统计学意义增加，而在塔里奎达处理的 Abcg2 大鼠中则显著（3.6 倍，p<0.0001）增加。同样，当 P-gp 和 BCRP 活性受损时，[C]厄洛替尼的脑摄取量也大大增加（4.5 倍，p<0.0001）。对于 [C]塔里奎达，各组之间 AUC 的差异指向与 [C]厄洛替尼相似的方向，但不太明显且缺乏统计学意义。我们的研究表明，在体内肺中存在功能性 P-gp 和 BCRP 活性，并进一步表明 P-gp 和 BCRP 在限制模型 P-gp/BCRP 底物的肺摄取方面具有功能冗余性，类似于血脑屏障。我们的研究结果表明，肺部外排转运蛋白对于吸入药物的疗效和安全性很重要，并且可以调节它们以改善肺部给药药物的药代动力学和药效学性能。
