Influence Of Lipophilicity Research Articles

Novel Techniques for Small Molecule-Based Drug Delivery in Cancerous Tissue: A Literature Review

Introduction: Small molecule cancer drugs target rapidly growing cancerous and healthy cells, leading to negative side effects. Due to the broad effects of small molecule drugs (SMDs), particularly on healthy cells, researchers have established methods such as altering lipophilicity, introducing drug conjugates, and nano-based drug delivery methods to diminish side effects. Methods: Relevant biomedical literature between 1991 to 2021 was obtained using Medline PubMed. Search terms were “physicochemical properties”, “nanotubes”, “liposomes”, and “small molecule drug conjugates”. Literature was selected based on pertinency after assessing the abstracts. Results: Properties such as a drug’s lipophilicity influence most SMD’s promiscuity. Controlling the hydrophobic features of lipophilic drugs within optimal ranges increases their specificity, half-life, and aqueous solubility. However, the narrow optimal range of lipophilicity makes it challenging to observe noticeable effects without reducing therapeutic effects. SMD conjugates improve drug delivery using a targeting ligand, and a therapeutic payload. The targeting ligand ensures greater binding to receptors on target tissues, such that a lower dose of a drug is required, thereby decreasing toxicity. SMD conjugates are non-immunogenic and have lower molecular weights, allowing for greater entry into solid tumours. Several nanomedical approaches have been developed to improve drug delivery. Carbon nanotubes, which exploit the enhanced permeability and retention effect, increase the accumulation of the drug at the cancerous tissue. Another method involves the use of liposomes, which exhibit high biocompatibility with cell membranes, low toxicity, and capability to carry hydrophobic as well as hydrophilic molecules. Discussion: While said novel therapies show increased targeting effects and decreased toxicity, notable limitations exist. Some SMD chemotherapeutics with high lipophilicity has been linked to adverse side effects. Conversely, lower lipophilicity ranges may reduce the permeability and potency of the drug. Alternatively, select SMD conjugates display poorer bioavailability, quick clearance, and multidrug resistance. Moreover, the toxicity of carbon nanotubes is not entirely deduced which may be associated with negative side effects. Conclusion: This systematic review emphasizes the importance of novel drug delivery systems to mitigate the toxic effects of small molecule cancer drugs through changes in lipophilicity, the introduction of drug conjugates, and nano-based drug delivery methods.

Effects of lipophilicity and functional groups of synthetic cannabinoids on their blood concentrations and urinary excretion

The influence of lipophilicity and functional groups of synthetic cannabinoids (SCs) on their blood concentrations and urinary excretion has been studied by analyzing blood and urine specimens sampled from drivers who were involved in a car crashes under the influence of SCs. A total of 58 specimens (26 urine and 31 blood specimens), sampled within 13h of the occurrence, were analyzed by liquid chromatography-tandem mass spectrometry. Fifteen SCs were detected in those specimens; the SCs detected were categorized as follows: Class 1, Naphthoyl/Benzoyl indole (EAM2201 and three other analogs); Class 2, Indole–3–carboxylate/carboxamide containing naphthol/quinol (5F–PB–22 and four other analogs); and Class 3, Indazole–3–carboxamide containing valine/tert–leucine derivative (5F–AMB and five other analogs). The calculated lipophilicity index log P, the octanol/water participation coefficient, of those SCs in Classes 1, 2, and 3 ranged between 5.01–8.14, 5.80–6.74 and 2.29–3.81, respectively. Class 3 SCs were detectable in 12 out of 13 urine specimens, but those in Classes 1 and 2 were not detected in urine. Our analytical results indicated that the boundary line for their detectability in urine lies between log P 4 and 5. The blood concentrations of Class 3 SCs varied widely (0.0036–31ng/ml) depending on their log P, while much smaller variation was observed among those in Class 2 (0.10–5.0ng/ml).

Synthesis, diuretic activity research and QSAR-analysis of N-(1,3,4-tiadiazol-2-il)substituted amides of alkanecarboxylic acids

Diuretics are effective drugs that are widely used in medicine, but have unwanted side effects. The derivative of thiadiazole – acetozolamide is a known diuretic. Therefore, the search for diuretics in this series and the establishment of quantitative «structure–activity» (QSAR) dependencies is appropriate.
 The aim of the work was to synthesis N-(1,3,4-thiadiazol-2-yl)substituted alkanes of alkanecarboxylic acids, study their diuretic activity, and QSAR analysis.
 The objects of the study were N-(1,3,4-thiadiazol-2-yl)substituted alkanes of alkanecarboxylic acids, obtained by the interaction of 2-amino-5-alkyl-1,3,4-thiadiazole with the corresponding acylchlorides. Investigation of diuretic activity of synthesized compounds was carried out by the method of Berchin. Hyper-Chem and BuildQSAR software were used for calculation of molecular descriptors and QSAR-models.
 Synthesis of 12 N-(1,3,4-thiadiazol-2-yl)substituted amides of alkanecarboxylic acids, the structure of which was confirmed by PMR spectroscopy and elemental analysis. Studies of diuretic activity showed that the synthesized compounds had pronounced diuretic properties, and some of them according to activity indicators were approaching or exceeding comparative preparations. Compound N-(5-methyl-[1,3,4]thiadiazol-2-yl) propionamide showed the best diuretic effect: increased daily diuresis in white rats, in comparison with intact control, in 2.47 times (p ≤ 0,001), in comparison with hydrochlorothiazide was in 1,6 times and acetazolamide was 1,75 times. The calculation of the molecular descriptors of N-(1,3,4-thiadiazol-2-yl)substituted amides of alkanecarboxylic acids was conducted. Based on the calculated values of molecular descriptors and diuretic activity values of 12 synthesized compounds, a QSAR analysis was performed. Analysis of structure-diuretic activity showed the greatest influence of lipophilicity, energy parameters, spatial structure and size of the molecule. Moreover, diuretic activity increases with increasing logP, decreasing the refractive, volume and area of the molecule, increasing the energy of the higher occupied molecular orbital. Increasing the charge on the Sulfur atom of the thiadiazole ring and the Оxygen atom of the carbonyl group, reducing the angle between the Sulfur atoms, the Nitrogen of the amide group and the Oxygen, and increasing the angle between the Nitrogene atoms of the thiadiazole ring, the Oxygen and the Nitrogen of the amide group, also increases diuretic activity.
 The results of the diuretic activity of the synthesized compounds N-(1,3,4-thiadiazol-2-yl)substituted amides of alkanecarboxylic acids show the potential for the search for diuretic agents among 1,3,4-thiadiazole derivatives. The resulting QSAR models will be used to modelling and prediction the activity of new potential diuretics.

Synthesis, characterisation and influence of lipophilicity on cellular accumulation and cytotoxicity of unconventional platinum(iv) prodrugs as potent anticancer agents.

Lipophilic platinum(iv) complexes were synthesised of the type [Pt(HL)(AL)(OH)(R)]2+ and [Pt(HL)(AL)(R)2]2+ (HL = 5,6-dimethyl-1,10-phenanthroline or 1,10-phenanthroline; AL = 1S,2S-diaminocyclohexane and R = increasingly lipophilic carboxylate axial ligands (C10-18)) from hydrophilic platinum(ii) precursors that exhibit exceptional anticancer activity. The increased overall lipophilicity of the complexes suggested the formation of spontaneously self-assembled structures in an aqueous environment. The anti-proliferative properties were assessed against one non-cancerous and a panel of cancerous cell lines. Nanomolar levels of activity were observed against several cell lines, with the lowest GI50 of 3.4 nm against the Du145 prostate cancer cell line and over 1100-fold greater activity than cisplatin against HT29 colon carcinoma. RP-HPLC was utilised to establish the relative lipophilicities of each complex. While there seemed to be an increase in cellular accumulation for the lipophilic derivatives in some instances, ICP-MS studies showed no clear correlation between increasing lipophilicity, cellular accumulation and cytotoxicity.

PHOTODYNAMIC INACTIVATION OF PATHOGENIC BACTERIA IN BIOFILMS USING NEW SYNTHETIC BACTERIOCHLORIN DERIVATIVES

Bacteriochlorins as the antimicrobial photosensitizers have a promising future in the face of the unrelenting increase in antimicrobial resistance. The goal of this study was to investigate the infl uence of lipophilicity and number of positively charged substituents in these molecules on the photodynamic inactivation (PDI) of biofi lm bacteria in vitro. Testing how bacteriochlorin derivatives with different properties affect microbes will allow to determine the optimal ratio of these parameters within a single molecule. We have investigated 4 bacteriochlorin derivatives, all of which were synthesized in Organic Intermediates and Dyes Institute. These were: hydrophobic neutral meso-tetra(3-pyridyl) bacteriochlorin (ВС1), amphyphilic tetracationic meso-tetra(1- undecyl-3-pyridyl)bacteriochlorin tetrabromide (ВС2), hydrophilic tetracationic meso-tetra[1-(4'-bromobutyl)-3-pyridyl]bacteriochlorin tetrabromide (ВС3) and octacationic meso-tetra[1-(4'-pyridiniobutyl) -3-pyridyl]bacteriochlorin octabromide (ВС4) . The water-soluble cationic bacteriochlorin derivatives showed the most effective PDI of bacteria in biofi lms. While tetracationic BC3 caused total inactivation of S. aureus 15, octacationic BC4 was bactericidal for P. aeruginosa 32 to the same degree (>99.999%). Interestingly, increasing the number of cationic substituents from 4 to 8 in bacteriochlorin molecules enhances bactericidal action against gram-negative bacteria in biofi lms. The lack of charge-carrying groups and high degree of lipophilicity of PS have negative impact on PDI of biofi lm bacteria. Bacterial membrane damage as a result of PDI can be one of the causes of cell death.

Passive Intestinal Absorption of Representative Plant Secondary Metabolites: A Physicochemical Study.

Natural products are generally ingested as part of traditional herbal decoctions or in the current diet. However, in natural product research, the bioavailability of secondary metabolites is often poorly investigated. In this work, a systematic study was carried out in order to highlight the physicochemical parameters that mainly influence the passive intestinal absorption of natural products. For this, a representative set of natural products including alkaloids, coumarins, flavonoid aglycones and glycosides, and carboxylic acids was selected and their physicochemical properties were predicted using relevant Volsurf+ descriptors. The chemical space obtained with this unbiased method was then correlated with experimental passive intestinal permeability data, which highlighted the main influence of lipophilicity, global hydrophilicity, size, and the ionisation state on passive intestinal absorption of natural products. Since the pH range encountered in the intestine is wide, the influence of the ionisation was investigated deeper experimentally. The ionisation state of weakly ionisable natural products, such as flavonoid aglycones, alkaloids, and carboxylic acids, was found to prevent the passive intestinal absorption of such natural products completely. In addition, the impact of solubility issues on passive permeability results was evaluated in cases of poorly water-soluble natural products, such as flavonoid aglycones and coumarins. The biomimetic fasted state simulated fluid-version 2 was found to improve the apparent solubility of such poorly soluble natural products without influencing their permeability behaviours. The use of such a solubilising buffer was found to be well adapted to the hexadecane membrane-parallel artificial membrane permeability assay and can circumvent the solubility issues encountered with poorly soluble natural products in such an assay.

Skin-mimetic chromatography for prediction of human percutaneous absorption of biologically active compounds occurring in medicinal plant extracts.

The main aim of this study was to predict quantitatively human percutaneous absorption of chosen compounds commonly occurring in plants which can be used as medicinal extracts in the drug and beauty industries. The most important human percutaneous descriptors, i.e. logKp (logarithm of the water/skin partition coefficient) and logJmax (logarithm of the maximum flux of solutes penetrating the skin), of fatty acids and polyphenols were determined using both in vitro and in silico methods. For in vitro determination of human percutaneous absorption, micellar liquid chromatography based on hexadecyltrimethylammonium bromide, sodium dodecyl sulfate and polyoxyethylene (23) lauryl ether (Brij35) was used. Human percutaneous absorption was characterized by entirely new QSAR/QRAR models based on retention, lipophilic, steric and electronic data as well as on the linear free energy relationship parameters. Many different correlations between human skin absorption and different physicochemical parameters were performed, e.g. the in silico estimated logKp value was correlated with the retention parameter logkw (logarithm of the retention factor extrapolated to pure water) from the systems imitating a cutaneous environment (R2 = 0.92). Moreover, the influence of lipophilicity on percutaneous absorption was examined. The obtained correlation was excellent (R2 = 0.95).

Influence of Lipophilicity on the Toxicity of Bisphenol A and Phthalates to Aquatic Organisms.

Bisphenol A (BPA) and phthalates are among the most popular plasticizers used today and have been reported ubiquitously in surface water, ground water, and sediment. For aquatic organisms, BPA was the most toxic (96h LC50s) to aquatic invertebrates (0.96-2.70mg/L) and less toxic to fish (6.8-17.9mg/L). The toxicity of BPA to amphibians differed among developmental stages, with embryos having an LC50 of 4.6-6.8mg/L and juveniles 0.50-1.4mg/L. The toxicity of phthalates is affected by aromatic ring substitution, alkyl chain length, and metabolism. The toxicity (96h LC50s) of phthalates was similar to aquatic invertebrates (0.46-377mg/L) and fish (0.48-121mg/L). In general, the toxicity of phthalates appears to be highest around a log KOW of 6, which corresponds to the highest potential for bioconcentration and bioaccumulation. In conclusion, the lipophilicity of BPA and phthalates influence their toxicity to aquatic species.

Synthesis of 2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-ones, their lipophilicity and anticancer activity in vitro

A new one-step synthesis of novel biologically active 2-substituted 2,4-dihydroxyphenyl-4[Formula: see text]-thieno[3,2-[Formula: see text]][1,3]thiazin-4-ones and 4[Formula: see text]-thieno[2,3-[Formula: see text]][1,3]thiazin-4-ones has been elaborated and described. The compounds were prepared by the reaction of aryl-modified sulfinylbis [(2,4-dihydroxyphenyl)methanethione]s and the corresponding aminothiophenecarboxamides. The derivatives showed anticancer activity in vitro. These compounds inhibited the proliferation and viability of lung cancer A549, colon cancer HT-29 and glioma C6 cells in a concentration-dependent manner. Some of the derivatives had no influence on normal skin fibroblasts culture viability. Moreover, one compound (1b) showed the ability to inhibit DNA synthesis in cancer cells, especially in C6 cells, and was not toxic for normal oligodendrocytes and hepatocytes. Using reversed phase RP18 HPLC and immobilised artificial membrane (IAM) chromatography the phase affinity of the compounds was determined. The influence of lipophilicity on the activity of compounds has been discussed.

In vitro and in silico determination of oral, jejunum and Caco-2 human absorption of fatty acids and polyphenols. Micellar liquid chromatography

In this investigation chosen saturated, mono- and polyunsaturated fatty acids as well as polyphenols have been analyzed.The main aim of this study was to determine oral, jejunum and Caco-2 human absorption of chosen fatty acids and polyphenols using in vitro and in silico methods. For in vitro determination of human drug absorption, the usefulness of Micellar Liquid Chromatography (MLC) with mobile phases containing different surfactants (including Brij35–Biopartitioning Micellar Chromatography (BMC)) has been confirmed.On the basis of Foley׳s equation, 1/k vs. CM correlations for the tested compounds have been done. Satisfactory linearity of the relationships was found over the whole eluents composition range studied with R2 approximately 0.99 in each case. Moreover, the analyte–micelle association constants (Kma) from Foley׳s equation have been compared for different micellar environments, containing Brij35, SDS and CTAB as a main component of micellar mobile phases. Completely new models describing human oral as well as Caco-2 and jejunum absorption have been constructed and compared with the cited models. These models are based on the Abraham descriptors and lipophilicity parameters as well as steric descriptors. Furthermore, many different correlations between physicochemical parameters and human intestinal absorption have been done, e.g. the correlation between human jejunum permeability estimated in silico and received using LSER parameters was excellent (R2 nearly 0.99).Chromatographic parameters have been collated with steric, electronic and physicochemical ones using QRAR (Quantitative Retention – Activity Relationships) and QSAR (Quantitative Structure – Activity Relationships) models. Moreover, retention BMC data have been compared with lipophilicity parameter logPo/w (n-octanol–water partition coefficient). The influence of lipophilicity on oral absorption (%) has been checked. The correlation between predicted oral absorption (%) and logPo/w has been done. Obtained R2 was 0.82.On the basis of chromatographic, lipophilicity, steric and different physicochemical parameters, the principal components analysis (PCA) has been done.

Lipophilic phthalocyanines for their potential interest in photodynamic therapy: synthesis and photo-physical properties

Several phthalocyanines with different peripheral substituents were prepared and characterized by MALDI-TOF, 1H NMR, UV–vis, fluorescence, and singlet oxygen quantum yields and retention time in HPLC normal phase. Zinc was used as a central metal ion to increase the photodynamic therapy efficiency. Phthalonitrile or 4-nitro phthalonitriles were used as starting materials. The influence of lipophilicity on the photophysical and photochemical properties was evaluated.

The Influence of Lipophilicity on the Classification of Antitumor Acridinones Evaluated by Principal Component Analysis

Principal component analysis (PCA) has been performed for some acridinone derivatives with antitumor activity to model relationships between structural descriptors and lipophilicity and their antileukemia activity. Principal component analysis obtained with the use of parameters of lipophilicity led to extract two main factors with eigenvalue higher than 1. The first principal component (factor 1) accounted for, by 84.3% of the variance in data and the second principal component (factor 2) explained 10.0% of data variance indicating that total data variance at the level 94.5% can be explained by the first two principal components. On the other hand, principal component analysis obtained with the use of parameters of lipophilicity together with some other molecular descriptors led to extract five main factors with eigenvalue higher than 1. In this case, the first principal component (factor 1) accounted for, by 62.64% of the variance in data, the second principal component (factor 2) explained 19.04% and the third principal component (factor 3) explained 8.49% of data variance indicating that total data variance at the level 90.17% can be explained by the first three principal components. Moreover, one of the most significant influences on the value of factors possessed parameters describing lipophilicity. However, some other descriptors considered in the study (some of constitutional, topological, molecular and geometrical one) could play an important role in the reflection of acridinone properties, too. More importantly, distribution of individual drugs on the plane determined by two and three principal components produced patterns in good agreement with their chemical structures as well as with their antitumor activity. Keywords: Acridinones, Antitumor activity, Compounds classification, Data variance, Lipophilicity, Molecular modeling, Principal component analysis (PCA), Statistical analysis, Structural descriptors, Varimax rotation

Structure-function relationships of the antibacterial activity of phenolic acids and their metabolism by lactic acid bacteria

To determine structure-function relationships of antibacterial phenolic acids and their metabolites produced by lactic acid bacteria (LAB). Minimum inhibitory concentrations (MICs) of 6 hydroxybenzoic and 6 hydroxycinnamic acids were determined with Lactobacillus plantarum, Lactobacillus hammesii, Escherichia coli and Bacillus subtilis as indicator strains. The antibacterial activity of phenolic acids increased at lower pH. A decreasing number of hydroxyl groups enhanced the activity of hydroxybenzoic acids, but had minor effects on hydroxycinnamic acids. Substitution of hydroxyl groups with methoxy groups increased the activity of hydroxybenzoic, but not of hydroxycinnamic, acid. Metabolism of chlorogenic, caffeic, p-coumaric, ferulic, protocatechuic or p-hydroxybenzoic acids by L. plantarum, L. hammesii, Lactobacillus fermentum and Lactobacillus reuteri was analysed by LC-DAD-MS. Furthermore, MICs of substrates and metabolites were compared. Decarboxylated and/or reduced metabolites of phenolic acids had a lower activity than the substrates. Strain-specific metabolism of phenolic acids generally corresponded to resistance. The influence of lipophilicity on the antibacterial activity of hydroxybenzoic acids is stronger than that of hydroxycinnamic acids. Metabolism of phenolic acids by LAB detoxifies phenolic acids. Results allow the targeted selection of plant extracts for food preservation, and selection of starter cultures for fermented products.

Influence of lipophilicity and chirality on the selectivity of ligands for beta 1- and beta 2-adrenoceptors.

Eudismic and QSAR analyses are reported for the beta 1- and beta 2-adrenoceptor affinities and beta 1-selectivity of 10 enantiomeric pairs of ligands with only N-isopropyl or N-t-butyl groups. For both receptors, the eudismic index (ratio of affinity) increases with the affinity of the eutomers. However, the affinity of the distomers for the beta 2-adrenoceptor is relatively high, suggesting additional hydrophobic interactions. This is confirmed by various correlations between affinities and lipophilicities, showing that the affinity for beta 2-adrenoceptors is slightly more dependent on lipophilicity than that for beta 1-adrenoceptors. As a result, the beta 1-selectivity of the investigated beta 1-adrenoceptor ligands is strongly and negatively correlated with their lipophilicity (r = -0.942).

Investigations into the Pharmacodynamic Effects of Dermally Administered Microemulsions Containing β-Blockers

Water uptake from the skin changes dermally applied near-saturated solutions of beta-blockers in microemulsion-bases into supersaturated microemulsions. Due to an enhanced thermodynamic activity, high absorption rates are expected from these preparations. The pharmacodynamic effect after dermal administration of such preparations has been evaluated using rabbits as a suitable in-vivo model. The dose dependency, influence of lipophilicity and of the thermodynamic activity of the drug is described. Assessment of dermal doses which were therapeutically equivalent to i.v. doses as, for example, shown with carazolol is possible. Although not all observed pharmacodynamic effects were due to these influences but rather due to the numerous other skin-vehicle-drug interactions which could not be explained with this model, the presented in-vivo model is helpful in evaluation of beta-blockers which were suitable candidates for transdermal administration.

Influence of Lipophilicity on the Renal Clearance of a Series of 5-Ethyl-5-Alkylbarbituric Acids in the Isolated Perfused Rat Kidney Preparation

Influence of Lipophilicity on the Renal Clearance of a Series of 5-Ethyl-5-Alkylbarbituric Acids in the Isolated Perfused Rat Kidney Preparation

Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations.

The highly lipophilic acyl-sulphonamides L-798106 and L-826266 showed surprisingly slow antagonism of the prostanoid EP₃ receptor system in guinea-pig aorta. Roles of affinity and lipophilicity in the onset kinetics of these and other prostanoid ligands were investigated. Antagonist selectivity was assessed using a panel of human recombinant prostanoid receptor-fluorimetric imaging plate reader assays. Potencies/affinities and onset half-times of agonists and antagonists were obtained on guinea-pig-isolated aorta and vas deferens. n-Octanol-water partition coefficients were predicted. L-798106, L-826266 and the less lipophilic congener (DG)-3ap appear to behave as selective, competitive-reversible EP₃ antagonists. For ligands of low to moderate lipophilicity, potency increments for EP₃ and TP (thromboxane-like) agonism on guinea-pig aorta (above pEC₅₀ of 8.0) were associated with progressively longer onset half-times; similar trends were found for TP and histamine H₁ antagonism above a pA₂ limit of 8.0. In contrast, L-798106 (EP₃), L-826266 (EP₃, TP) and the lipophilic H₁ antagonists astemizole and terfenadine exhibited very slow onset rates despite their moderate affinities; (DG)-3ap (EP₃) had a faster onset. Agonism and antagonism on the vas deferens EP₃ system were overall much faster, although trends were similar. High affinity and high liphophilicity may contribute to the slow onsets of prostanoid ligands in some isolated smooth muscle preparations. Both relationships are explicable by tissue disposition under the limited diffusion model. EP₃ antagonists used as research tools should have moderate lipophilicity. The influence of lipophilicity on the potential clinical use of EP₃ antagonists is discussed.

Influence of lipophilicity on drug partitioning into sclera, choroid-retinal pigment epithelium, retina, trabecular meshwork, and optic nerve.

In vitro bovine eye tissue/phosphate-buffered saline, pH 7.4, partition coefficients (Kt:b), in vitro binding to natural melanin, and in vivo delivery at 1 h after posterior subconjunctival injection in Brown Norway rats were determined for eight beta-blockers. The Kt:b was in the order intact tissue, dry weight method >or= intact tissue, wet weight method corrected for tissue water and drug in tissue water >> intact tissue, wet weight method > homogenized tissue. In intact tissue methods, Kt:b followed the order choroid-retinal pigment epithelium (RPE) > trabecular meshwork > retina > sclera approximately optic nerve; propranolol > betaxolol > pindolol approximately timolol approximately metoprolol > sotalol approximately atenolol approximately nadolol. Intact tissue, wet weight log (Kt:b) correlated positively with log D for all tissues (R(2) of 0.7-0.9). Log (melanin binding capacity) correlated positively with choroid-RPE log (Kt:b) (R(2) of 0.5). With an increase in concentration, Kt:b decreased in trabecular meshwork for all beta-blockers and for some lipophilic beta-blockers in choroid-RPE and sclera. With an increase in drug lipophilicity, in vivo tissue distribution increased in choroid-RPE, iris-ciliary body, sclera, and cornea but exhibited a declining trend in retina, vitreous, and lens. In vitro bovine intact tissue, wet weight Kt:b correlated positively with rat in vivo tissue/vitreous humor distribution for sclera, choroid-RPE, and retina (R(2) of 0.985-0.993). In vitro tissue partition coefficients might be useful in predicting in vivo drug distribution after trans-scleral delivery. Less lipophilic solutes exhibiting limited nonproductive binding in choroid-RPE might exhibit greater trans-scleral delivery to the retina and vitreous.

Vacuolar ATPase-Mediated Cellular Concentration and Retention of Quinacrine: A Model for the Distribution of Lipophilic Cationic Drugs to Autophagic Vacuoles

The antiprotozoal agent quinacrine is a lipophilic cationic drug highly distributed to tissues. It has been used in the present experiments to examine whether the vacuolar and autophagic cytopathology induced by organic amines is independent from the therapeutic class. Furthermore, we tested the presence of the concentrated cationic drug itself in the enlarged vacuoles by exploiting the intense green fluorescence of quinacrine. Finally, the influence of lipophilicity on the apparent affinity of amine pseudotransport has been addressed by comparing quinacrine to another substituted triethylamine, procainamide. Quinacrine was concentration-dependently taken up by human smooth muscle cells (cytosolic granular-vacuolar morphology at and above 25 nM; in cell extracts, uptake nearly maximal in 2 h, apparent K(m) of 8.7 microM). The vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine uptake by cells or released the cell-associated drug in preloaded cells. The lipidated (II) form of microtubule-associated protein light chain 3 accumulated at and above a quinacrine concentration of 2.5 microM (4 h), indicating the conserved macroautophagic nature of the vacuolar cytopathology, although vacuole size was modest. The enlarged vacuoles containing quinacrine excluded cherry fluorescent protein; many vacuoles were lined with cherry fluorescent protein-conjugated Rab7, a GTPase associated with late endosomes/lysosomes. Taken together, these results are compatible with the transition of quinacrine-concentrating vacuoles toward an autophagolysosome identity. Quinacrine is concentrated in cells via V-ATPase-mediated ion trapping with an apparent affinity approximately 500-fold higher than that of the less lipophilic drug procainamide, and, despite the small size of ensuing vacuoles, the macroautophagic signature of this cytopathology was observed.

Double-armed crown ethers for calcium optical sensors

This paper presents the characterization of optical sensing membranes for calcium based on ionophore–chromoionophore chemistry. Six different ionophores, 18-membered crown ether derivatives, were studied, coming from 18-crown-6 ether and 4,13-diaza-18-crown-6 ether to a series of double-armed crown ethers with different type of terminal groups. The study of optical membranes containing the same transducer and plasticizer allow drawing some conclusions on the influence of lipophilicity and size of the terminal group of the side chain on calcium selectivity. We have calculated the exchange constant K exch I L p for each equilibrium with alkaline and alkaline-earth ions and the selectivity coefficient k I , J Osel for each ion against calcium as a way for a full characterization of sensing membranes. In all cases the ion:ionophore stability constants for calcium were the highest and the ionophore V containing an (N-adamantylcarbamoyl) acetyl moiety originated the most selective membrane for calcium. Analytical parameters for calcium determination using prepared membranes were calculated.