Bacillus stearothermophilus, a useful model to evaluate membrane interactions of lipophilic drugs, adapts to the presence of amiodarone in the growth medium. Drug concentrations in the range of 1^2 WM depress growth and 3 WM completely suppresses growth. Adaptation to the presence of amiodarone is reflected in lipid composition changes either in the phospholipid classes or in the acyl chain moieties. Significant changes are observed at 2 WM and expressed by a decrease of phosphatidylethanolamine (relative decrease of 23.3%) and phosphatidylglycerol (17.9%) and by the increase of phosphoglycolipid (162%). The changes in phospholipid acyl chains are expressed by a decrease of straight-chain saturated fatty acids (relative decrease of 12.2%) and anteiso-acids (22%) with a parallel increase of the iso-acids (9.8%). Consequently, the ratio straight-chain/branched iso-chain fatty acids decreases from 0.38 (control cultures) to 0.30 (cultures adapted to 2 WM amiodarone). The physical consequences of the lipid composition changes induced by the drug were studied by fluorescence polarization of diphenylhexatriene and diphenylhexatriene-propionic acid, and by differential scanning calorimetry. The thermotropic profiles of polar lipid dispersions of amiodarone-adapted cells are more similar to control cultures (without amiodarone) than those resulting from a direct interaction of the drug with lipids, i.e., when amiodarone was added directly to liposome suspensions. It is suggested that lipid composition changes promoted by amiodarone occur as adaptations to drug tolerance, providing the membrane with physico-chemical properties compatible with membrane function, counteracting the effects of the drug. ß

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Partition coefficients of DDE (2,2-bis(p-chlorophenyl)-1,1-dichloroethylene) were determined, in model and native membranes, as a function of temperature, lipid chain length, cholesterol content and DDE concentration, by means of second derivative ultraviolet spectrophotometry. DDE incorporation increases with the temperature, since the partition values in dimyristoylphosphatidylcholine (DMPC), at 24, 30 and 37 degrees C, are 5722 +/- 138, 10356 +/- 763 and 14006 +/- 740, respectively. The insecticide incorporates better into bilayers of DMPC as compared with DPPC (dipalmitoylphosphatidylcholine). The partition decreases from 10355 +/- 763 in DMPC to 6432 +/- 613 in DPPC, at temperatures 5-7 degrees C above the midpoint of their transitions. The addition of cholesterol to fluid membranes of DMPC depresses the partition of DDE. In agreement with the results in models of synthetic lipids, the partition of DDE into native membranes increases with the temperature and decreases with the intrinsic cholesterol. It is concluded that a fluid membrane favors the accumulation of DDE.

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The effects of DDT (0‐100 μM) in pure phospholipid and phospholipid/cholesterol bilayers were investigated by fluorescence polarization of 1,6‐diphenyl‐1,3,5‐hexatriene (DPH), a probe located in the bilayer interior, and by excimer to monomer fluorescence intensity ratio (I′/I) of 1,3‐di(l‐pyrenyl)propane (Py(3)Py), a probe sitting closer to the polar region. In the gel phase of dimyristoylphosphatidylcholine (DMPC) bilayers, DDT induces concentration‐dependent fluidizing effects into the hydrophobic membrane regions, but no effects are observed in the outer regions of the membrane, as evaluated by DPH and Py(3)Py, respectively. Furthermore, in the fluid phase of DMPC and for DDT concentrations higher than 10 μM, I′/I of Py(3)Py decreases, reflecting an order increase of the probe environment and DPH fails to detect any apparent effect. Similar effects were observed in other pure lipid bilayers, namely dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC). Unlike DPH, Py(3)Py is very sensitive to DPPC and DSPC pre‐transitions which are not abolished by 50 μM DDT. This DDT concentration inhibits to some extent the cholesterol‐induced ordering in DMPC bilayers and high cholesterol concentrations (⩾ 30 mol%) do not prevent insecticide interaction, as evaluated by DPH. On the other hand, the effects of DDT reported by Py(3)Py depend on temperature and cholesterol content of DMPC bilayers. Thus, for cholesterol levels ranging from 10 to 50 mol% and for temperatures below the phase transition temperature of DMPC, Py(3)Py fails to detect any significant effect. Nevertheless, above the phase transition temperature of DMPC, Py(3)Py detects either ordering effects of DDT at low cholesterol contents (< 20 mol%) or fluidizing DDT effects at high cholesterol levels (> 20 mol%).