Comparison of kinetics of chlorImipramine, desmethylImipramine and Imipramine accumulation in “single pass” isolated perfused rat lungs

Abstract

Pulmonary uptake, efflux and metabolism of three tricyclic antidepressants, chiorImipramine (CIM), desmethylimipramine (DMI) and Imipramine (IMP) were investigated. The isolated rat lungs were artificially ventilated and perfused via pulmonary artery with non-recirculating perfusate containing the radiolabeled test drug (10 μM) at a constant flow (10 ml/min) for 10 min. After that, the perfusate was switched to drug-free medium for 10 min. The effluent was collected at 20-sec intervals with a fraction collector. Total radioactivity in the effluent was counted by liquid scintillation spectrometry,and metabolism analyses were carried out for the perfusate and lung according to differential extraction method. The uptake and efflux rates of these antidepressants were resolved into at least two exponential components. The amounts of CIM, DMI and IMP taken up for 10 min were 433 ± 10, 400 ± 14, 353 ± 9 nmol/g lungjand total amounts of CIM, DMI and IMP effused back into the circulation were 68 ± 5, 72 ± 7, 95 ± 4 nmol/g lung, respectively. The amounts of the drugs remaining in the lung after the uptake-efflux experiment were 366 ± 10, 328 ± 7, 259 ± 11 nmol/g lung for CIM, DMI and IMP, respectively. Approximately 3% of CIM and 6% of IMP were identified as the corresponding N-oxides after a 20 min perfusion for uptake and efflux. No metabolites other than N-oxides were detected in the perfusate and lung. These results suggest that the affinity for the lung tissue is in the following descending order: CIM, DMI and IMP, and that tertiary amines CIM and IMP are metabolized via N-oxidation even during a single passage,but a secondary amine DMI is not metabolized by the rat lung at all.