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

Abstract

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...

The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators

“…Microcalorimetry demonstrated that only ECg (63) and (-)-EGCg (64) were able to change the main phospholipid phase transitions of DMPC, whereas EC (37b) and (+)-catechin (C) (36a) were inactive in this respect. This was in agreement with measured liposome : buffer partition coefficients that were substantially higher for ECg (63) and EGCg (64) than for C (36) and EC (37). Both ECg (63) and EGCg (64) reduced T m and caused calorimetric peak broadening.…”

“…Positive entropy change was attributed to the enhancement of disorder in the acyl chain region of the bilayer caused by phenothiazine ring insertion. The affinity of CPZ (9) and triflupromazine (11) for model membranes containing, apart from PC, also phosphatidylserine (PS) or phosphatidylethanolamine (PE) was studied by the same group [36]. It was observed that partition coefficient values for both drugs were slightly reduced when PE was present in the liposomes.…”

Recent development in derivative ultraviolet/visible absorption spectrophotometry: 2004–2008

“…Multivariate calibration methods applied to monitoring of enzymatic synthesis; UV spectra and their first-order derivatives used as input data for models PCR and PLS; comparison with HPLC [227] Barbiturates By solid-phase extraction with celite and UV differential DS; 2nd-derivative spectrum of pH 14 solution measured with pH 10 solution as reference; in blood, urine and liver; recovery studies 100% for blood and urine; 78.4-102% for liver; RSD < 2.9% [228] Chlorophyll and astaxanthin In Haematococcus pluvialis cells by 1st derivative; comparison with HPLC; RSD 1.2% and 1.1%, respectively [229] Anti-inflammatory steroid drugs Partition coefficients determined by 2nd derivative [230] Triflupromazine and chlorpromazine Effects of phosphatidylserine and phosphatidylethanolamine content on partitioning of drugs between phosphatidylcholine-aminophospholipid bilayer vesicles and water studied by 2nd derivative [231] Triflupromazine and chlorpromazine Effects of inorganic salts, NaCl, NaBr, NaI, Na2SO4, KCl, KBr, KI, on the binding constants of drugs to bovine serum albumin by 2nd derivative [232] ingredients in this article were two couples, sulphamethoxazole and trimethoprim, and hydrochlorothiazide and captopril.…”

Effect of Long-Chain Fatty Acids on the Binding of Triflupromazine to Human Serum Albumin: A Spectrophotometric Study

“…To determine the association constants of drugs to biological macromolecules such as BSA [8–11], liposomes [12–14], and lipid-emulsions [15] in buffer solutions, we have usually employed a second-derivative spectrophotometric method [16–19], since it can entirely eliminate the effects of background signals caused by the signals of macromolecules to offer a flat and zero-level baseline. In the previous studies [8, 9] to examine the phenothiazine drug-BSA binding, the binding constant was obtained by applying a simple partition-like nonspecific binding model, though the 19 F NMR results showed that the TFZ-BSA binding involves specific Site II binding.…”