Previous work has established that pulmonary accumulation of chlorphentermine (CP), an anorexigenic agent, results in impaired pulmonary clearance of 5-HT and NE. CP-induced phospholipidosis results in greater accumulation of CP and other pneumophilic drugs, impairment of pulmonary flavin monooxygenase (PFMO) catalyzed N-oxidation of imipramine and chlorpromazine, thus blocking the pulmonary elimination process since, normally, the N-oxide products lose the affinity exhibited by the parent compounds for the lung tissue. Considerable species differences exist in PFMO. These findings have been shown in perfused lungs as well as in in vivo preparations of rats and rabbits. Amiodarone, a member of another class of drugs, is an antiarrhythmic agent known to cause pulmonary disease in patients, accompanied by phospholipidosis, the mechanism and consequences of which are unknown. The proposed studies are designed to continue our efforts to investigate the mechanisms underlying the drug-induced phospholipidosis and the pulmonary sequestration of pneumophilic drugs, mechanisms of impaired nonrespiratory and respiratory function of the lung.
The specific aims are to investigate: a) the influence of CP-induced phospholipidosis on the clearance of 5-HT and exogenous chemicals using in vivo rat preparations; b) the mechanism of drug-induced pulmonary phospholipidosis; c) the effects of amiodarone-induced phospholipidosis on amiodarone uptake and on uptake and clearance of other endogenous and exogenous chemicals; d) the effect of amiodarone and CP-induced phospholipidosis on pressure-volume relationships; and e) the possible physiological roles of PFMO with purified rat lung FMO. These studies are expected to lead to a better understanding of the mechanisms involved in pulmonary drug accumulation, and the consequences on pulmonary functions.
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