Thermodynamics of Partitioning of Phenothiazine Drugs between Phosphatidylcholine Bilayer Vesicles and Water Studied by Second-Derivative Spectrophotometry

Takegami, Shigehiko; Kitamura, Kazuya; Kitade, Tatsuya; Kitagawa, Ai; Kawamura, Kikuko

doi:10.1248/cpb.51.1056

Cited by 20 publications

(17 citation statements)

References 20 publications

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“…As seen in Table 2, the lipid–water partition coefficients calculated for a membrane packing density of π M =27 mN m −1 are in excellent agreement with those measured for small unilamellar POPC vesicles by means of ITC 10. The lipid–water partition coefficients for the promazine analogues have also been measured by means of spectrophotometric techniques and are also in good agreement (if transformed to the same units) 26…”

Section: Discussionmentioning

confidence: 99%

Halogenation of Drugs Enhances Membrane Binding and Permeation

et al. 2004

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Halogenation of drugs is commonly used to enhance membrane binding and permeation. We quantify the effect of replacing a hydrogen residue by a chlorine or a trifluoromethyl residue in position C-2 of promazine, perazine, and perphenazine analogues. Moreover, we investigate the influence of the position (C-6 and C-7) of residue CF(3) in benzopyranols. The twelve drugs are characterized by surface activity measurements, which yield the cross-sectional area, the air-water partition coefficient, and the critical micelle concentration. By using the first two parameters (A(D) and K(aw)) and the appropriate membrane packing density, the lipid-water partition coefficients, are calculated in excellent agreement with the lipid-water partition coefficients measured by means of isothermal titration calorimetry for small unilamellar vesicles of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. Replacement of a hydrogen residue by a chlorine and a trifluoromethyl residue enhances the free energy of partitioning into the lipid membrane, on average by deltaG(lw) approximately -1.3 or -4.5 kJ mol(-1), respectively, and the permeability coefficient by a factor of approximately 2 or approximately 9, respectively. Despite exhibiting practically identical hydrophobicities, the two benzopyranol analogues differ in their permeability coefficients by almost an order of magnitude; this is due to their different cross-sectional areas at the air-water and lipid-water interfaces.

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Section: Discussionmentioning

confidence: 99%

Halogenation of Drugs Enhances Membrane Binding and Permeation

et al. 2004

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“…The increase of the half-life of decameric vanadate upon increasing the protein concentration can be rationalized in terms of a complex formation between decameric vanadate and G-actin. Considering two equilibrium reactions, one between V10 and V1 and the other between V10 and the protein, and taking into account that the first one is much slower (time scale of hours) than the second (time scale of seconds or minutes at most) we can deduce that the velocity of decomposition of decameric vanadate species is inversely proportional to the increase of the protein concentration [37][38][39]. Almost a plateau of the half-life time was reached for Gactin concentration between 4 and 8 lM, and for 10 lM of decameric vanadate species, thus suggesting that the Gactin:V10 stoichiometry is approximately one or higher, contrarily to sarcoplasmic reticulum calcium ATPase with about five decameric vanadate molecules per calcium pump (Fig.…”

Section: Stabilization Of Decameric Vanadate By G-actin Under Polymermentioning

confidence: 99%

Decavanadate interactions with actin: Inhibition of G-actin polymerization and stabilization of decameric vanadate

Ramos

Manuel

Tiago

et al. 2006

Journal of Inorganic Biochemistry

101

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Decameric vanadate species (V10) inhibit the rate and the extent of G-actin polymerization with an IC50 of 68 ± 22 lM and 17 ± 2 lM, respectively, whilst they induce F-actin depolymerization at a lower extent. On contrary, no effect on actin polymerization and depolymerization was detected for 2 mM concentration of ''metavanadate'' solution that contains ortho and metavanadate species, as observed by combining kinetic with 51 V NMR spectroscopy studies. Although at 25°C, decameric vanadate (10 lM) is unstable in the assay medium, and decomposes following a first-order kinetic, in the presence of G-actin (up to 8 lM), the half-life increases 5-fold (from 5 to 27 h). However, the addition of ATP (0.2 mM) in the medium not only prevents the inhibition of G-actin polymerization by V10 but it also decreases the half-life of decomposition of decameric vanadate species from 27 to 10 h. Decameric vanadate is also stabilized by the sarcoplasmic reticulum vesicles, which raise the half-life time from 5 to 18 h whereas no effects were observed in the presence of phosphatidylcholine liposomes, myosin or G-actin alone. It is proposed that the ''decavanadate'' interaction with G-actin, favored by the G-actin polymerization, stabilizes decameric vanadate species and induces inhibition of G-actin polymerization. Decameric vanadate stabilization by cytoskeletal and transmembrane proteins can account, at least in part, for decavanadate toxicity reported in the evaluation of vanadium (V) effects in biological systems.

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“…16) Measurements of Absorption and Second Derivative Spectra The sample solutions containing 15 mM of TFZ or CPZ and various amounts of the vesicle suspension were prepared in a similar manner to that of the previous papers. 11,17,18) The reference solutions were those prepared without the drug. Absorption and second derivative spectra were obtained by similar ways as in the previous papers.…”

Section: Measurement Of Mean Diameter Of the Vesiclesmentioning

confidence: 99%

“…Absorption and second derivative spectra were obtained by similar ways as in the previous papers. 11,[17][18][19] …”

Section: Measurement Of Mean Diameter Of the Vesiclesmentioning

confidence: 99%

Effects of Phosphatidylserine and Phosphatidylethanolamine Content on Partitioning of Triflupromazine and Chlorpromazine between Phosphatidylcholine-Aminophospholipid Bilayer Vesicles and Water Studied by Second-Derivative Spectrophotometry

et al. 2005

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Partition coefficients of drugs between lipid bilayer vesicles (liposomes) and water provide fundamental information relating to the drug interactions with biomembranes. Especially, information on the drug partitioning helps understanding the pharmacodynamics and pharmacokinetics of drugs, because most of drugs usually partition into cell membrane by passive diffusion. In the quantitative structure-activity relationship (QSAR) studies of drugs, it has been suggested that the partition coefficients obtained for the liposome system are more effective than those obtained for the n-octanol/water system. [1][2][3] Triflupromazine (TFZ) and chlorpromazine (CPZ) are known as major antipsychotropic drugs of the phenothiazine derivatives and exert their action by antagonizing neuronal D 2 receptor in the brain. Recently, CPZ has been shown to hold promise as a pharmacotherapeutic agent for prion-based afflictions.4) We previously reported the partition coefficients (K p s) of some phenothiazine drugs including TFZ and CPZ for phosphatidylcholine (PC) small unilamellar vesicles (SUV) determined by second-derivative spectrophotometry. 5)The derivative method has been recognized to eliminate the effect of background signals 6,7) and usefully applied to the determination of the partition coefficients of drugs between lipid vesicles and water without the troublesome separation procedures [8][9][10] that may disturb the equilibrium states. Using SUV and large unilamellar vesicles (LUV) prepared from PC and cholesterol, the effects of vesicle size and cholesterol content in the bilayer membranes on the K p values of CPZ and TFZ were also studied by the second-derivative spectrophotometry. 11)A recent fluorescence study by Chen et al. provides that the hydrophobic nature of CPZ drives its general association with membranes, while the cationic nature of CPZ promotes its preferential association with phosphatidylserine (PS) in the bilayer membranes.12) Also, Elferink 13) and Dachary-Prigent 14) reported that CPZ bound preferentially to PC liposomes containing PS, compared to PC liposomes.PS is contained abundantly in the brain and nerve cell membranes as compared to the other organs. While phosphatidylethanolamine (PE), an aminophospholipid as PS and the second major phospholipid component after PC, is distributed widely all over the organs in the body and concerned with the membrane fusion and permeability.Therefore, the effects of these aminophospholipids, PS and PE, on the interactions of phenothiazine drugs with phospholipid bilayer vesicles should be investigated quantitatively, since the quantitative evaluation of the difference in the affinity of the drugs for PC, PS and PE will offer important information to understand their distribution and accumulation in the body.In this study we examined the effects of aminophospholipid contents and vesicle size on the partitioning of TFZ and CPZ into the vesicles (SUV and LUV) by using second-derivative spectrophotometry. Experimental Calculation of Molar Partition CoefficientsThe mol...

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Thermodynamics of Partitioning of Phenothiazine Drugs between Phosphatidylcholine Bilayer Vesicles and Water Studied by Second-Derivative Spectrophotometry

Cited by 20 publications

References 20 publications

Halogenation of Drugs Enhances Membrane Binding and Permeation

Halogenation of Drugs Enhances Membrane Binding and Permeation

Decavanadate interactions with actin: Inhibition of G-actin polymerization and stabilization of decameric vanadate

Effects of Phosphatidylserine and Phosphatidylethanolamine Content on Partitioning of Triflupromazine and Chlorpromazine between Phosphatidylcholine-Aminophospholipid Bilayer Vesicles and Water Studied by Second-Derivative Spectrophotometry

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