Inhaled 99mTc-Sestamibi clearance from Lungs and its relation to the expression of P-glycoprotein and Multidrug Resistance Protein-1

Abstract

1. Abstract P-glycoprotein (P-gp) and Multidrug Resistance Protein (MRP1) are the key cellular drug efflux transporters in a range of tissues and the radiopharmaceutical 99mTc-sestamibi has been demonstrated to be a substrate for both transporters in a number of in vivo and in vitro studies. The elimination rate of 99mTc-sestamibi from the lungs following inhalation as an aerosol has been shown to be delayed in healthy smokers versus non-smokers. It was hypothesized that this was the result of smoke-induced up-regulation of P-gp. The aims of this study were: To examine the relationship between the lung elimination rate of inhaled sestamibi and immuno-histochemical expression of broncho-pulmonary MRP1 and P-gp. To study the repeatability of the technique and assess the effect of various demographic factors affecting the clearance of inhaled sestamibi. Methods: Thirty-five participants were included in the study. They all underwent an inhaled 99mTc-sestamibi clearance study. Of these, 13 were patients undergoing surgery for primary lung cancer (5/13) or spontaneous pneumothorax (8/13). There were 22 healthy volunteers. All participants gave informed consent prior to the study. Semi-quantitative assessment (grade 0-3) of MRP1 and P-gp expression in lung on immuno-histochemical examination was correlated with the elimination rate of sestamibi from the lung tissue. The effect of various factors on inhaled sestamibi clearance including smoking status, age, gender and locality of residence was evaluated. The study was repeated in 10 participants to assess the repeatability and inter-observer reproducibility of the technique. Results: MRP1 expression was seen in 12/13 patients while P-gp in only 2/13. The mean sestamibi elimination rate was faster in patients expressing low levels of MRP1 expression (grade 0-1), mean T½ of 105 ± 20 min, compared with those with higher levels of MRP1 expression (grade 2-3), mean T½ of 149 ± 28 min (P = 0.008). Inhaled sestamibi clearance was significantly delayed in smokers (n=17), mean T½ = 142 ± 29 min, compared to non smokers (n=18), mean T½ = 91 ± 14 min (P < 0.0001). The clearance of inhaled sestamibi was also significantly delayed in non smoking older patients >30 y (n= 6), mean T½ = 101 ± 15 min, compared to younger patients <30 y (n=12), mean T½ = 86 ± 11 min (P < 0.05), and in non smoking men (n=7), T½ = 130 ± 37 min, compared to women (n=11), T½ = 105 ± 28 min (P < 0.05). There was however no significant difference noted between urban dwellers from London (n=22), mean T½ = 89 ± 11 min, compared to semi-rural dwellers (n=13), mean T½ = 96 ± 20 min (P > 0.05). Bland-Altman analysis revealed excellent agreement between test and re-test values with a (bias) of 4.8 min and a standard deviation of the difference (precision) of 5.7 min. There was an excellent inter-observer reproducibility seen with a Spearman Rho value of 0.96 and p<0.05 Conclusion: The study results indicate a significant correlation between the predominant transporter in lung (broncho-alveolar epithelium) MRP1 and inhaled 99mTc- Sestamibi clearance. Inhaled 99mTc- Sestamibi clearance is a safe and reproducible technique. Smoking, increasing age and male gender appear to significantly prolong the lung clearance of inhaled sestamibi. There was however no definite effect of environmental status on the clearance rate observed

Date of Award	2016
Original language	English
Awarding Institution	King's College London
Supervisor	Jim Ballinger (Supervisor) & Prof Adrien Michael Peters (Supervisor)