Partition of N‐Monodemethylated Phenothiazine Drugs to Phosphatidylcholine Bilayer Vesicles Studied by Second‐Derivative Spectrophotometry

Takegami, Shigehiko; Kitamura, Kazuya; Takahashi, Keiko; Kitade, Tatsuya

doi:10.1002/jps.10121

Cited by 15 publications

(20 citation statements)

References 16 publications

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“…In membrane studies, the unilamellar vesicles are mostly used because of better defined and simpler structures. Limitations such as a complicated kinetics with difficult-topredict duration of transport for some compounds, 1 tedious separation, 2,3 laborious spectroscopic data analysis due to the light scatter if the separation step is omitted, [4][5][6] or the stability of some preparations 7 make liposomes less suitable for a high-throughput screening (HTS). Embedding of liposomes in gel beads 8 alleviates the problem of liposome separation but introduces the risk of the matrix effects.…”

Section: Liposomesmentioning

confidence: 99%

Drug-Membrane Interactions Studied in Phospholipid Monolayers Adsorbed on Nonporous Alkylated Microspheres

et al. 2007

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Characterization of interactions with phospholipids is an integral part of the in vitro profiling of drug candidates because of the roles the interactions play in tissue accumulation and passive diffusion. Currently used test systems may inadequately emulate the bilayer core solvation properties (immobilized artificial membranes [IAM]), suffer from potentially slow transport of some chemicals (liposomes in free or immobilized forms), and require a tedious separation (if used for free liposomes). Here the authors introduce a well-defined system overcoming these drawbacks: nonporous octadecylsilica particles coated with a self-assembled phospholipid monolayer. The coating mimics the structure of the headgroup region, as well as the thickness and properties of the hydrocarbon core, more closely than IAM. The monolayer has a similar transition temperature pattern as the corresponding bilayer. The particles can be separated by filtration or a mild centrifugation. The partitioning equilibria of 81 tested chemicals were dissected into the headgroup and core contributions, the latter using the alkane/water partition coefficients. The deconvolution allowed a successful prediction of the bilayer/water partition coefficients with the standard deviation of 0.26 log units. The plate-friendly assay is suitable for high-throughput profiling of drug candidates without sacrificing the quality of analysis or details of the drug-phospholipid interactions.

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Section: Liposomesmentioning

confidence: 99%

Drug-Membrane Interactions Studied in Phospholipid Monolayers Adsorbed on Nonporous Alkylated Microspheres

et al. 2007

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“…About a hundred and fifty methods for individual and simultaneous determination drugs have been reported over the last few years. 170 [324][325][326][327][328][329][330][331][332][333][334][335][336] Since the lipid vesicles intense background signals by light scattering, the determination of partition coefficients of drugs to lipid bilayer with normal spectrophotometric methods was very difficult. In derivative UV/VIS spectrophotometry, the spectral changes were enhanced as well as elimination of the residual background signal effects.…”

Section: ·3 Pharmaceutical Analysismentioning

confidence: 99%

“…331 The partition coefficients of three N-monodemethylated metabolites of phenothiazines between phosphatidylcholine vesicles and water were determined to evaluate their affinity to biomembranes by second-DS. 332 Moreover, the interactions of chlorpromazine and triflupromazine with bovine serum albumin were studied. 333 The effect of lecithin on the partition coefficients of amphiphilic drugs (β-blockers, atenolol and nadolol) in mixed bile salt/lecithin micelles was studied by DS.…”

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confidence: 99%

Recent Developments of Derivative Spectrophotometry and Their Analytical Applications

El‐Sayed

El-Salem

2005

ANAL. SCI.

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The zero-crossing derivative spectra method is the most common procedure for the simultaneous determination of binary mixtures of their overlapping spectra. As an example, the derivative spectra of binary mixtures of phospho-and silicomolybdenum blue are illustrated in Fig. 1. 23 By measuring the derivative values (heights h1 in Fig. 1) for mixtures of phosphate and silicate at 806 nm (zero-crossing wavelength of silicomolybdate complex), one can avoid the interference by silicate and the phosphate concentration can be determined. By measuring the derivative values (heights h2 in Fig. 1 Moreover, one disadvantage of the zero-crossing method is the necessity of selecting critical wavelengths for the measurements. This selection causes considerable loss of sensitivity and precision in case of binary mixtures. The so-called "ratio spectra derivative" permits the use of the wavelengths corresponding to maximum or minimum and also the use of the distance between consecutive maximum and minimum, thus avoiding these problems. 24 Salinas et al. 25 developed a derivative quotient spectra method with a standard divisor when the spectra of the components are overlapped. The method was based on dividing the spectrum for a mixture into the standard spectra for each of the analyses and driving the quotient to obtain a spectrum that is independent of the analyte concentration used as a divisor. The use of standardized spectra as divisors minimizes experimental errors and background noise. 26 An accurate choice of standard divisors and working wavelengths is fundamental for several reasons. 25,27,28 Easy measurements on separate peaks, higher values of the analytical signals and no need to work only at zero-crossing points (sometimes co-existing compounds have no maximum or minimum at these wavelengths) are advantages for ratio spectra derivative spectrophotometry in comparison with the zerocrossing derivative spectrophotometry. Also, the presence of a lot of maxima and minima in ratio spectra derivative data was another advantage, since these wavelengths give an opportunity for the determination of these compounds in the presence of other active compounds and excipients that possibly interfered with the assay. 29 2·1 Resolution of binary and ternary mixtures by applyingderivative ratio spectra (derivative quotient spectra) The absorption spectrum of a mixture of three compounds; A, B and C is determined by this equation:AM,λ i = εA,λ i CA + εB,λ i CB + εC,λ i CC (path-length is 1 cm)where, AM,λ i is the absorbance value of the mixture at wavelength λi, εA,λ i , εB,λ i and εC,λ i are the molar absorptivities of A, B and C at λi, CA, CP and CC are the molar concentrations of A, B and C, respectively. When we divide this spectrum by the spectrum of a standard solution of one of the components (e.g., A of concentration CA). That is bywe obtainThe first derivative of this spectrum ratio givesIf CC = 0, we have the binary mixture of A and B, and the spectrum in this case is:In Eq. (5) we can see that the derivative ratio spectrum of...

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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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Partition of N‐Monodemethylated Phenothiazine Drugs to Phosphatidylcholine Bilayer Vesicles Studied by Second‐Derivative Spectrophotometry

Cited by 15 publications

References 16 publications

Drug-Membrane Interactions Studied in Phospholipid Monolayers Adsorbed on Nonporous Alkylated Microspheres

Drug-Membrane Interactions Studied in Phospholipid Monolayers Adsorbed on Nonporous Alkylated Microspheres

Recent Developments of Derivative Spectrophotometry and Their Analytical Applications

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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