Pharmacokinetics of 99mTc-HMPAO in isolated perfused rat lungs. J Appl Physiol (1985) 2019 Nov 01;127(5):1317-1327
Date
08/16/2019Pubmed ID
31414953Pubmed Central ID
PMC6957362DOI
10.1152/japplphysiol.00717.2018Scopus ID
2-s2.0-85074742957 (requires institutional sign-in at Scopus site)Abstract
Lung uptake of technetium-labeled hexamethylpropyleneamine oxime (HMPAO) increases in rat models of human acute lung injury, consistent with increases in lung tissue glutathione (GSH). Since 99mTc-HMPAO uptake is the net result of multiple cellular and vascular processes, the objective was to develop an approach to investigate the pharmacokinetics of 99mTc-HMPAO uptake in isolated perfused rat lungs. Lungs of anesthetized rats were excised and connected to a ventilation-perfusion system. 99mTc-HMPAO (56 MBq) was injected into the pulmonary arterial cannula, a time sequence of images was acquired, and lung time-activity curves were constructed. Imaging was repeated with a range of pump flows and perfusate albumin concentrations and before and after depletion of GSH with diethyl maleate (DEM). A pharmacokinetic model of 99mTc-HMPAO pulmonary disposition was developed and used for quantitative interpretation of the time-activity curves. Experimental results reveal that 99mTc-HMPAO lung uptake, defined as the steady-state value of the 99mTc-HMPAO lung time-activity curve, was inversely related to pump flow. Also, 99mTc-HMPAO lung uptake decreased by ~65% after addition of DEM to the perfusate. Increased perfusate albumin concentration also resulted in decreased 99mTc-HMPAO lung uptake. Model simulations under in vivo flow conditions indicate that lung tissue GSH is the dominant factor in 99mTc-HMPAO retention in lung tissue. The approach allows for evaluation of the dominant factors that determine imaging biomarker uptake, separation of the contributions of pulmonary versus systemic processes, and application of this knowledge to in vivo studies.NEW & NOTEWORTHY We developed an approach for studying the pharmacokinetics of technetium-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) in isolated perfused lungs. A distributed-in-space-and-time computational model was fit to data and used to investigate questions that cannot readily be addressed in vivo. Experimental and modeling results indicate that tissue GSH is the dominant factor in 99mTc-HMPAO retention in lung tissue. This modeling approach can be readily extended to investigate the lung pharmacokinetics of other biomarkers and models of lung injury and treatment thereof.
Author List
Clough AV, Barry K, Rizzo BM, Jacobs ER, Audi SHAuthor
Said Audi PhD Professor in the Biomedical Engineering department at Marquette UniversityMESH terms used to index this publication - Major topics in bold
AnimalsLung
Male
Organ Culture Techniques
Radiopharmaceuticals
Rats
Rats, Sprague-Dawley
Technetium Tc 99m Exametazime
Tomography, Emission-Computed, Single-Photon
