Pulmonary elimination rate of inhaled ^99mTc‐sestamibi radioaerosol is delayed in healthy cigarette smokers

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Very little is known about the physiology of P‐glycoprotein (P‐gp) expression in the lungs. • Ex vivo evidence based on resected lung tissue suggests that pulmonary P‐gp is upregulated by cigarette smoke, but there are no in vivo studies to date. WHAT THIS STUDY ADDS • The novel observation that healthy cigarette smokers have a delayed pulmonary elimination rate of inhaled 99mTc‐sestamibi, a P‐gp substrate, provides for the first time a potential method for quantifying functional pulmonary P‐gp expression that may inform about drug therapy by inhalation as well as provide a non‐invasive, quantitative, human biomarker for assessing P‐gp modulators. AIM To explore inhaled technetium‐99m‐labelled hexakis‐methoxy‐isobutyl isonitrile (99mTc‐sestamibi) for quantifying pulmonary P‐glycoprotein (P‐gp) expression. METHODS The elimination rate from the lungs of 99mTc‐sestamibi was recorded scintigraphically for 30 min following inhalation as an aerosol in healthy smokers, nonsmokers and patients with lung disease. RESULTS 99mTc‐sestamibi elimination rates [% min−1 (SD; P vs. healthy nonsmokers)] were: healthy nonsmokers, 0.43 (0.083); healthy smokers, 0.19 (0.056; P < 0.001); chronic obstructive pulmonary disease patients, 0.26 (0.077; P < 0.001). Elimination rates in three patients with interstitial lung disease were not accelerated. CONCLUSION Cigarette smoke upregulates lung P‐gp. 99mTc‐sestamibi elimination in normal smokers could be used to test new P‐gp modulators. The findings also have implications for inhaled drug delivery.

Does the Clearance of Inhaled99mTc-Sestamibi Correlate with Multidrug Resistance Protein 1 Expression in the Human Lung?

“…They observed that it was significantly slower than the clearance of the hydrophilic radioaerosol, Tcpentetate (25), and hypothesized that the delayed clearance of 99m Tc-sestamibi was due to expression of P-gp in the airway epithelium (26). The clearance rate of inhaled 99m Tc-sestamibi from the lungs was further significantly delayed in healthy smokers versus nonsmokers, and it was hypothesized that this was the result of smoke-induced up-regulation of P-gp (25). …”

“…Recently, Ruparelia et al measured the clearance rate of 99m Tc-sestamibi following inhalation as an aerosol from normal lungs in healthy nonsmoking humans (25). They observed that it was significantly slower than the clearance of the hydrophilic radioaerosol, Tcpentetate (25), and hypothesized that the delayed clearance of 99m Tc-sestamibi was due to expression of P-gp in the airway epithelium (26).…”

“…Timeactivity curves were generated for both lungs from the geometric mean of the data. While analysis of the clearance was performed only on the posterior views of the lungs in the previous study (25), we used a geometric mean from anterior and posterior view as this would provide a more accurate measure of the clearance, partly accounting for the depth-dependency of the activity distribution of the radiopharmaceutical and differential photon attenuation.…”

“…An exponential fit to the data was applied, while in the previous study by Ruparelia et al (25) a linear fit was used. This was to avoid any assumptions, especially with the early part of the curve, which in the previous study (25) was not included.…”

“…An exponential fit to the data was applied, while in the previous study by Ruparelia et al (25) a linear fit was used. This was to avoid any assumptions, especially with the early part of the curve, which in the previous study (25) was not included. In this study, the imaging was commenced within a minute of completing inhalation, while in the previous study the imaging was commenced 6 minutes after completion of inhalation.…”