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ß-Blockers and Benzodiazepines Location in SDS and Bile Salt

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ß-Blockers and Benzodiazepines Location in SDS and Bile Salt Journal of Pharmaceutical and Biomedical Analysis 45 (2007) 62–69 ␤-Blockers and benzodiazepines location in SDS and bile salt micellar systems An ESR study Salette Reis a,∗, Carla Guimaraes˜ Moutinho b, Eulalia´ Pereira c, Baltazar de Castro c, Paula Gameiro c, Jose´ L.F.C. Lima a a REQUIMTE, Departamento de Qu´ımica-F´ısica, Faculdade de Farm´acia, Universidade do Porto, 4099-030 Porto, Portugal b Faculdade de Ciˆencias da Sa´ude, Universidade Fernando Pessoa, 4200-150 Porto, Portugal c REQUIMTE, Departamento de Qu´ımica, Faculdade de Ciˆencias, Universidade do Porto, 4169-007 Porto, Portugal Received 2 February 2007; received in revised form 18 May 2007; accepted 21 May 2007 Available online 25 May 2007 Abstract The work here described aimed to find out the location of the different species of two families of pharmaceutical substances, namely two ␤-blockers (atenolol and nadolol) and two benzodiazepines (midazolam and nitrazepam) in synthetic (sodium dodecyl sulphate, SDS) and natural (bile salts-sodium cholate and sodium deoxycholate) micellar aggregate solutions. Electronic spin resonance spectroscopy studies were carried out, at 25 ◦C and at an ionic strength of 0.10 M in NaCl, using 5-, 12- and 16-doxylstearic acid probes (AS). The immobilization degree of solubilized stearic acid spin probes was found to vary with the position of the nitroxide group in the sequence 5-doxylstearic acid > 12-doxylstearic acid > 16- doxylstearic acid for SDS and 12-doxylstearic acid > 5-doxylstearic acid > 16-doxylstearic acid for both bile salts investigated. Therefore, from the rotational correlational time values obtained, it can be inferred that the structure of bile salt micelles is markedly different from that of SDS micelles and the results suggest that the bile salt micelles studied have similar structure independently of differences in the molecular structure of the respective bile salts. Drug location studies were performed at pH 4.0 (SDS solutions) or 7.0 (bile salt solutions) and 10.8 in order to study the effect of the drug ionisation on its relative position on micelles. The results have shown that drug location is controlled by the (i) drug hydrophilicity and acid/base properties, with the more soluble compound in water (atenolol) exhibiting smaller variation of rotational correlational time (in SDS and bile salts solutions), and with both ␤-blockers exhibiting smaller deviations in the protonated forms and (ii) the bile salt monomers, with the dihydroxylic bile salt (deoxycholate) producing larger differences. The work described herein allow us to conclude that the (protonated) ␤-blockers are probably located on the surface of the detergent micelles, and linked to them by means of essentially electrostatic forces, while the (neutral) benzodiazepines are probably located deeper in the interior of the micelles. © 2007 Elsevier B.V. All rights reserved. Keywords: ␤-Blockers; Benzodiazepines; SDS; Bile salts; Micelles; ESR spectroscopy; Doxylstearic acid probes 1. Introduction intestinal hydrolysis and also act as emulsifying and solubi- lizing agents for neutral fats [1–3]. The term bile acid covers Bile acids participate in many different physiological pro- several derivatives of cholic acid which differ in the number and cesses. For example, the salts of these acids are involved in position of ␣-hydroxyl substituents. The acids have a rigid and planar “cholesterol like” ring structure which is solubilized in water by glycine or taurine residues [4]. When bile salts are dissolved in water, they form micellar ∗ Corresponding author at: Faculdade de Farmacia,´ Departamento de Qu´ımica-F´ısica, Rua An´ıbal Cunha, 164, 4050 Porto, Portugal. aggregates above a critical concentration (cmc) as do linear ionic Tel.: +351 222 078 966; fax: +351 222 004 427. surfactants [5–8]. Typical ionic detergents such sodium dodecyl E-mail address: [email protected] (S. Reis). sulphate (SDS) contain a flexible linear chain and aggregate in 0731-7085/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jpba.2007.05.023 S. Reis et al. / Journal of Pharmaceutical and Biomedical Analysis 45 (2007) 62–69 63 spherical or ellipsoidal micelles with the paraffin chains forming concentrations (cmc). The information concerning micellar a liquid hydrocarbon core with a charged surface [9]. In contrast, interior construction as well as micellar size is necessary to inter- bile salt micelles have neutral surface with a high amount of pret the behaviour of drug solubilization by bile salt micelles hydroxyl groups exposed to the aqueous phase. The micelles can [29]. be crudely depicted by broad cylinders: the hydrophobic part of Recent works include the application of spin label studies the steroids form the core whereas the hydroxy and carboxylate on the interactions of several compounds in heterogeneous sys- groups project from the outside walls [10,11]. tems, giving complementary structural information and allowing Because the molecular structure of bile salts is very different the sites of drug location in different environment (micellar from that of conventional detergents [9,12], the bile salts exhibit or bilayer) to be draw. The authors have demonstrated that unique behaviour with respect to self-association, aggregation theses spectroscopy techniques are a valuable tool to inves- and molecular solubilization [1]. Size and aggregation number tigate changes in the backbone conformation and dynamics. is usually much smaller than those of micelles formed by alkyl This may be of major importance, for instance, for pep- chain detergents [13–15]. tides and small proteins when they bind to cell membranes In conventional detergents, solubilization sites include the [30–32]. micellar surface, the palisade layer and the hydrophobic inner At present, however, information on the micellar location core [16]. Analogous binding sites are not present in the smaller, of pharmaceutical drugs in emulsification agents used in phar- more rigid bile salt micelles [12,13,17]. Instead, solubilization maceutical industry is not complete. Thus, we tried to, on the of hydrophobic compounds is accomplished through favourable one hand, obtain more information on micellar interior struc- interactions with the hydrophobic surfaces of the bile salt ture of bile salts by using the spin label method, which has micelles, primarily at the C18 and C19 sites. The resulting solubi- already been applied to examine the interior states of biological lization microenvironment in bile salt micelles are highly apolar membranes, liposomes, bile salt-lecithin mixed micelles, and [12,18]. synthetic surfactants such as sodium dodecyl sulfate and hex- Many pharmacologically active compounds are amphiphilic adecyltrimethylammonium bromide [33,34]. On the other hand, or hydrophobic molecules, including phenothiazines and ben- three doxylstearic acid probes were used to study the location of zodiazepine, tranquilizers, analgesics, antibiotics, tricyclic the different species of two ␤-blockers (atenolol and nadolol) antidepressants, antihistamines, anticholinergics, ␤-blockers, and of two benzodiazepines (midazolam and nitrazepam) in local anesthetics [19,20]. These compounds may undergo differ- micellar solutions of two bile salts, sodium cholate and sodium ent kinds of association, and their site of action in the organism deoxycholate, and one synthetic detergent, sodium dodecyl is frequently the plasma membrane. Even if their target is intra- sulphate. The paramagnetic centres of 5- and 16-doxylstearic cellular, the interaction with this first barrier plays a fundamental acid spin labels are, respectively, near the micelle/water inter- role [19]. In this manner, the position and orientation of the drug face and deep within the micelle bilayer, and incorporation of in the bilayer is of great importance, especially when the drug these spin probes into micelles results in distinctive EPR spec- can act directly on the membrane, or can interact with molecules tra. located in it, like enzymes or receptors. Advances in the understanding of the effect of drugs on the 2. Experimental structural and dynamical properties of membrane components have been achieved through the use of spectroscopic (EPR, 2.1. Reagents and solutions NMR, fluorescence, Fourier transform infrared) and other bio- physical techniques (X-ray and neutron diffraction, differential All compounds were used as received: ␤-blockers (atenolol scanning calorimetry (DSC), titration calorimetry) [21]. and nadolol) and bile salts (sodium cholate and sodium The use of spectroscopic probes, which are located at differ- deoxycholate), from Sigma. Benzodiazepines (midazolam and ent depths in the membrane and whose spectral characteristics nitrazepam) were kindly provided by Hoffman-La Roche, are sensitive to the surrounding environment, is particularly sodium dodecyl sulphate, from Aldrich, and all other chem- suited for studies with natural and model membranes, micelles icals were from Merck (grade pro analysi). Solutions were or proteins [21–25]. These probes can be used to determine prepared with double deionized water (conductivity less than proximity relationships within the membrane, as well as to eval- 0.1 ␮Scm−1). uate quantitatively the interaction of drugs with the bilayer. Spin probes 5-, 12- and 16-doxylstearic acid (doxyl = 4,4- Generally, the molecular probes are chosen for their spectro- dimethyl-3-oxazolidinyloxy) (abbreviated as 5-AS, 12-AS and scopic handles and the ability to interpret the observations 16-AS, respectively)
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