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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL020622-09
Application #
3336189
Study Section
Toxicology Study Section (TOX)
Project Start
1977-05-01
Project End
1991-04-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
9
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
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Kodavanti, U P; Mehendale, H M (1991) Amiodarone- and desethylamiodarone-induced pulmonary phospholipidosis, inhibition of phospholipases in vivo, and alteration of [14C]amiodarone uptake by perfused lung. Am J Respir Cell Mol Biol 4:369-78
Kodavanti, U P; Mehendale, H M (1990) Cationic amphiphilic drugs and phospholipid storage disorder. Pharmacol Rev 42:327-54
Rao, S B; Mehendale, H M (1990) Comparative evaluation of sequestration of polyamines by perfused rabbit and rat lungs. Indian J Exp Biol 28:1166-70
Kodavanti, U P; Lockard, V G; Mehendale, H M (1990) In vivo toxicity and pulmonary effects of promazine and chlorpromazine in rats. J Biochem Toxicol 5:245-51
Joshi, U M; Rao, P; Kodavanti, S et al. (1989) Fluorescence studies on binding of amphiphilic drugs to isolated lamellar bodies: relevance to phospholipidosis. Biochim Biophys Acta 1004:309-20
Camus, P; Joshi, U M; Lockard, V G et al. (1989) Effects of drug-induced pulmonary phospholipidosis on lung mechanics in rats. J Appl Physiol 66:2437-45
Rao, S B; Mehendale, H M (1988) Passive sequestration of putrescine, spermidine and spermine by rat lungs. Biochim Biophys Acta 966:22-9
Joshi, U M; Kodavanti, P R; Mehendale, H M (1988) Glutathione metabolism and utilization of external thiols by cigarette smoke-challenged, isolated rat and rabbit lungs. Toxicol Appl Pharmacol 96:324-35
Joshi, U M; Kodavanti, P R; Coudert, B et al. (1988) Types of interaction of amphiphilic drugs with phospholipid vesicles. J Pharmacol Exp Ther 246:150-7

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