Types of interaction of amphiphilic drugs with phospholipid vesicles.
Binding characteristics of nine amphiphilic drugs, which induce pulmonary phospholipidosis, to L-alpha-dipalmitoyl phosphatidylcholine (DPPC) vesicles were studied using fluorescence probes, 1,6-diphenyl-1,3,5-hexatriene and 1-anilino-8-naphthalene sulfonate (ANS) for hydrophobic and hydrophilic interactions, respectively. Drug binding to DPPC was quantitated using Scatchard analysis. The tested drugs bound to DPPC with different capacities. The order of binding capacity to hydrophobic site of DPPC using 1,6-diphenyl-1,3,5-hexatriene as fluorescence probe was promethazine greater than amiodarone greater than chlorpromazine greater than chloramphenicol greater than imipramine greater than trimipramine greater than propranolol much greater than chloroquine and chlorphentermine. Two binding affinities were evident for amiodarone, chlorpromazine, imipramine, trimipramine and promethazine. The order of binding strength at high affinity site was amiodarone greater than trimipramine greater than chlorpromazine greater than promethazine greater than imipramine. The order of drug binding capacity using ANS as fluorescence probe was chlorphentermine greater than trimipramine greater than propranolol much greater than amiodarone, chloroquine and chloramphenicol. Each of these drugs displayed a single binding affinity. Imipramine and chlorpromazine at 1 mM and higher concentrations showed intense fluorescence with ANS (5-20 microM) in the absence of DPPC indicating an interaction of these drugs with ANS. Chloroquine did not bind to either sites on DPPC. The binding of these drugs and their interactions with hydrophobic or hydrophilic sites of DPPC were correlated with their capacity to induce pulmonary phospholipidosis. These results indicate that not all the drugs which bind to DPPC in vitro induce phospholipidosis in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Joshi
U M
UM
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson.
Kodavanti
P R
PR
Coudert
B
B
Dwyer
T M
TM
Mehendale
H M
HM
D000638:Amiodarone / Q000009:adverse effects / Q000378:metabolism; D000817:Anilino Naphthalenesulfonates; D001665:Binding Sites; D002701:Chloramphenicol / Q000009:adverse effects / Q000378:metabolism; D002738:Chloroquine / Q000009:adverse effects / Q000378:metabolism; D002746:Chlorpromazine / Q000009:adverse effects / Q000378:metabolism; D004161:Diphenylhexatriene; D007099:Imipramine / Q000009:adverse effects / Q000378:metabolism; D008064:Lipidoses / Q000139:chemically induced*; D008171:Lung Diseases / Q000139:chemically induced*; D008563:Membrane Lipids / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D011398:Promethazine / Q000009:adverse effects / Q000378:metabolism; D011433:Propranolol / Q000009:adverse effects / Q000378:metabolism; D013501:Surface-Active Agents / Q000009:adverse effects / Q000378:metabolism*; D014299:Trimipramine / Q000009:adverse effects / Q000378:metabolism
D000817:Anilino Naphthalenesulfonates; D008563:Membrane Lipids; D010743:Phospholipids; D013501:Surface-Active Agents; D004161:Diphenylhexatriene; C027132:1-anilino-8-naphthalenesulfonate; D002701:Chloramphenicol; D014299:Trimipramine; D002738:Chloroquine; D011433:Propranolol; D011398:Promethazine; D000638:Amiodarone; D007099:Imipramine; D002746:Chlorpromazine