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Log P (log + p)
Terms modified by Log P Selected AbstractsA quantitative approach to probe the dependence and correlation of food-effect with aqueous solubility, dose/solubility ratio, and partition coefficient (Log P) for orally active drugs administered as immediate-release formulationsDRUG DEVELOPMENT RESEARCH, Issue 2 2005Brahma N. Singh Abstract The purpose of the present review was to systematically evaluate if aqueous solubility, dose/solubility ratio, and partition coefficient (Log P) could be used as useful parameters to quantitatively probe the dependence and correlation of in vivo food effects with these physicochemical properties of orally active drugs administered as immediate-release (IR) formulations. Mean AUC data obtained under fasted and fed states of over 100 structurally diverse orally active drugs with different physicochemical properties were obtained from the primary literature. Correlations of AUC ratio (Fed/Fasted) with aqueous solubility, dose/solubility ratio, and Log P were derived and statistically evaluated by Pearson's correlation test (two-tailed). A negative correlation was obtained between the logarithm of the aqueous solubility and the AUC ratio (r=,0.5982, N=93), whereas a positive correlation existed between AUC ratio and Log P (r=0.5147, N=110) and between AUC ratio and dose/solubility ratio (r=0.5511, N=87). All these correlations were significant (P<0.0001). Based on this study, the estimated range within which a drug is not expected to be significantly affected by food falls between 0.148,89.39 mg/ml for aqueous solubility and between 0.23,624 ml for the dose:solubility ratio. The corresponding range of Log P for expecting a lack of food-effect lies between ,1.13 and 2.98. Quantitatively, the effect of food was most pronounced for lipophilic, poorly water-soluble drugs (with only a few exceptions), irrespective of whether the drug is acidic, basic, or neutral. It is concluded that aqueous solubility, dose/solubility ratio, and partition coefficient can be used as useful parameters to probe the dependence and correlation of food-effect with these physicochemical parameters for immediate-release formulations. Drug Dev. Res. 65:55,75, 2005. © 2005 Wiley-Liss, Inc. [source] A QSAR analysis of toxicity of Aconitum alkaloidsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004Angélica M. Bello-Ramírez Abstract Biological activity of Aconitum alkaloids may be related to their toxicity rather than to a specific pharmacological action. A Quantitative structure-activity relationships (QSAR) analysis was performed on the following two groups of alkaloids: compounds with an aroyl/aroyloxy group at R14 position (yunaconitine, bulleyaconitine, aconitine, beiwutine, nagarine, 3-acetyl aconitine, and penduline), and compounds with the aroyloxy group at R4 position (N -deacetyllappaconitine, lappaconitine, ranaconitine, N -deacetylfinaconitine, N -deacetylranaconitine). The LD50 (,mol/kg) of the 12 alkaloids were obtained from the literature. LD50 was significantly lower in group 1 than in group 2. The steric and core,core repulsion energies were significantly higher in group 1. The total energy and heat of formation and electronic energies were significantly lower in group 1. The reactivity index of N, C1,, C4, and C6, were similar between groups. The reactivity index of C2, was significantly higher and the reactivity index of C3, and C5, were significantly lower in group 1. Log P and pKa were similar between groups. Molecular weight was significantly higher in group 1. A significant linear relationship was observed between log LD50 and either analgesic log ED50 or local anesthetic log ED50. The LD50/analgesic ED50 obtained from average values was 5.9 for group 1 and 5.0 for group 2. However, the LD50/local anesthetic ED50 was 40.4 and 318, respectively. The study supports that the analgesic effects of these alkaloids are secondary to their toxic effects whereas alkaloids from group 2 are susceptible to be further studied as local anesthetic agents. [source] Comparison of ethylammonium formate to methanol as a mobile-phase modifier for reversed-phase liquid chromatographyJOURNAL OF SEPARATION SCIENCE, JSS, Issue 5 2006Martin M. Waichigo Abstract Ethylammonium formate (EAF), (C2H5NH3+HCO2,), is a room-temperature ionic liquid that has a polarity similar to that of methanol (MeOH) or acetonitrile. The separation at 1 mL/min of a test mixture of vitamins or phenols on a polystyrene-divinylbenzene column using either an EAF- or MeOH-water mobile phase is similar in terms of both resolution and analysis time. Because the viscosity of EAF is higher than that of MeOH, the plate count for phenol at room temperature is lower by about a factor of 1.1,1.4 depending on the flow rate. However, van Deemter plots show that this loss in plate count at 1 mL/min can be recovered and improved from 1500 to 2400 plates by working at a slightly elevated temperature of 55°C. A slower flow rate such as 0.8 mL/min can also substantially improve the plate count as compared to 1,1.5 mL/min. Log P (octanol partition coefficient) versus log k, data for a variety of neutral test solutes are again similar whether EAF or MeOH is used as the organic modifier. Resolution of certain peak pairs such as 2,4-dinitrophenol/2,4,6-trinitrophenol and p -aminobenzoate/benzoate is enhanced using EAF as compared to MeOH. One advantage of EAF is that control of retention of solutes such as water-soluble vitamins under totally aqueous mobile phase conditions is environmentally preferable for quality control applications. In addition, EAF seems to be a milder mobile-phase modifier than MeOH for certain proteins such as lysozyme. [source] Effect of solute lipophilicity on penetration through canine skinAUSTRALIAN VETERINARY JOURNAL, Issue 12 2003PC MILLS Objective To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series of alcohols through canine skin Design Skin harvested from Greyhound thorax was placed in Franz-type diffusion cells and the in vitro passage of radio-labelled (14C) alcohols (ethanol, butanol, hexanol and octanol (Log P 0.19 - 3.0)) through separate skin sections was measured in replicates of five. Permeability coefficient (kP, cm/h), maximum flux (Jmax, mol/cm2/h) and residue remaining within the skin were determined. Results The kP increased with increasing lipophilicity (6.2 times 10 -4± 1.6 times 10 -4 cm/h for ethanol to 1.8 times 10 -2± 3.6 times 10 -3 cm/h for octanol). Alcohol residues remaining within each skin sample followed a similar pattern. An exponential decrease in Jmax with increasing lipophilicity was observed. Conclusion Changes in canine skin permeability occur with increasing alcohol lipophilicity. This finding has practical consequences for the design of topical formulations and optimisation of drug delivery through animal skin. [source] Artificial Neural Networks and the Study of the Psychoactivity of Cannabinoid CompoundsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2010Káthia M. Honório Cannabinoid compounds have widely been employed because of its medicinal and psychotropic properties. These compounds are isolated from Cannabis sativa (or marijuana) and are used in several medical treatments, such as glaucoma, nausea associated to chemotherapy, pain and many other situations. More recently, its use as appetite stimulant has been indicated in patients with cachexia or AIDS. In this work, the influence of several molecular descriptors on the psychoactivity of 50 cannabinoid compounds is analyzed aiming one obtain a model able to predict the psychoactivity of new cannabinoids. For this purpose, initially, the selection of descriptors was carried out using the Fisher's weight, the correlation matrix among the calculated variables and principal component analysis. From these analyses, the following descriptors have been considered more relevant: ELUMO (energy of the lowest unoccupied molecular orbital), Log P (logarithm of the partition coefficient), VC4 (volume of the substituent at the C4 position) and LP1 (Lovasz,Pelikan index, a molecular branching index). To follow, two neural network models were used to construct a more adequate model for classifying new cannabinoid compounds. The first model employed was multi-layer perceptrons, with algorithm back-propagation, and the second model used was the Kohonen network. The results obtained from both networks were compared and showed that both techniques presented a high percentage of correctness to discriminate psychoactive and psychoinactive compounds. However, the Kohonen network was superior to multi-layer perceptrons. [source] O -2,,3,-Ketal-Nucleolipids of the Cytostatic 5-Fluorouridine: Synthesis, Lipophilicity, and Acidic StabilityHELVETICA CHIMICA ACTA, Issue 8 2010Edith Malecki Abstract The synthesis of a series of cyclic and acyclic O -2,,3,-ketal derivatives of the cancerostatic 5-fluorouridine (2a) is described. The novel compounds were characterized by 1H- and 13C-NMR, and UV spectroscopy, as well as by elemental analyses. The lipophilicity values (log P, retention times in RP-18 HPLC) of the cyclic ketals were determined and related to the ring tensions as well as the acid stability of the spiro-linked ketal rings. [source] Effect of octanol:water partition coefficients of organophosphorus compounds on biodistribution and percutaneous toxicity,,JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 5 2006Steven E. Czerwinski Abstract Knowledge of partition coefficient (log P) data can play a critical role in understanding the pharmacokinetic and pharmacodistributive properties of toxic organophosphorus (OP) compounds. Using a recently published gas chromatographic method, the octanol:water log P values for the compounds tabun (GA), sarin (GB), cyclosarin (GF), and O -ethyl- S -(2-diisopropylaminoethyl) methylphosphonothiolate (VX) were determined to be 0.384 ± 0.033, 0.299 ± 0.016, 1.038 ± 0.055, and 0.675 ± 0.070, respectively. Based on these data, the log P value of the fluorophosphonate fragment, common to GB, soman (GD), and GF, was determined to be ,2.256 ± 0.273. The predictive value for absorption and distribution of the determined log P values was compared to measured values. The time to onset of local fasciculations (47.3, 29.0, 8.8, 8.5, and 6.3 min, respectively) in guinea pigs exposed percutaneously to equilethal doses of GA, VX, GF, GB, or GD was used as an indicator of dermal penetration. There was a good correlation (r = 0.95) between the measured log P value and the rate of onset of local fasciculations. Assuming a direct correspondence, equilibrium tissue:blood log P may be estimated from octanol:water log P. Comparison of the estimated and directly measured tissue:blood log P revealed a correlation of 0.8 for GD in liver, muscle, and adipose tissue. Our results demonstrate the use of log P data to both predict absorption and determine the distribution of OP compounds in tissues. This facilitates further estimates of in vivo OP effects from in vitro experiments. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:241,246, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20140 [source] Tobramycin and Gentamycin elution analysis between two in situ polymerizable orthopedic compositesJOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 1 2003M. DiCicco Abstract This research analyzed Tobramycin and Gentamycin elution characteristics for two antibiotic-impregnated bone composites: PMMA-based Simplex P® and the novel, hybrid, bioactive, CORTOSSÔ. Experimental results were correlated with composite hydrophilicity and antibiotic phase partitioning behaviors. The phase partitioning experiment was conducted to understand antibiotic solubility in aqueous environments. By comparing experimental results with calculated data, antibiotic release behavior was predicted. Total Tobramycin elution percentages from CORTOSS and Simplex P were 12.5 and 6.4%, respectively. Total Gentamycin elution percentages from CORTOSS and Simplex P were 6.95 and 10.17%, respectively. Phase partitioning data indicate 100% of Tobramycin remains in aqueous phases, being extremely hydrophilic. This is supported by its calculated theoretical value (log P = , 7.32). Results suggest that Tobramycin elution can be attributed to composite hydrophilicity as well as its high degree of hydrophilicity. Fifteen percent of Gentamycin distributes in hydrophobic phases (log P = , 4.22). Despite a lower Gentamycin hydrophilicity, its release was affected by its complexation with polar salts in the leaching buffer, thereby increasing its elution potential, making it appreciably water soluble. CORTOSS is more hydrophilic; therefore the migration of aqueous liquids into the polymer network of CORTOSS facilitates greater antibiotic elution compared with hydrophobic Simplex P. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 65B: 137,149, 2003 [source] G-protein coupled receptors: SAR analyses of neurotransmitters and antagonistsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2004C. L. Kuo MS Summary Background:, From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (, - and , -), dopaminergic, serotoninergic (5-HT1,5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. Objective:, The aim of the present study is to examine the structure,activity relationships of agents acting on G-protein coupled receptors. Method:, Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' desk reference; M.J. O'Neil (2001) The Merck index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), Elumo (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), Ehomo (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (Hb) (donors and receptors), were chosen as molecular descriptors for SAR analyses. Results:, The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and , as independent variables. Conclusion:, It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors. [source] Ab initio computational study of positron emission tomography ligands interacting with lipid molecule for the prediction of nonspecific bindingJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 14 2008Lula Rosso Abstract Nonspecific binding is a poorly understood biological phenomenon of relevance in the study of small molecules interactions in vivo and in drug development. Nonspecific binding is thought to be correlated in part to a molecule's lipophilicity, typically estimated by measuring (or calculating) octanol,water partition coefficient. This is, however, a gross simplification of a complex phenomenon. In this article, we present a computational method whose aim is to help identify positron emission tomography (PET) ligands with low nonspecific binding characteristics by investigating the molecular basis of ligand,membrane interaction. We considered a set consisting of 10 well-studied central nervous system PET radiotracers acting on a variety of molecular targets. Quantum mechanical calculations were used to estimate the strength of the interaction between each drug molecule and one phospholipid molecule commonly present in mammalian membranes. The results indicate a correlation between the computed drug,lipid interaction energy and the in vivo nonspecific distribution volume relative to the free tracer plasma concentration, calculated using standard compartmental modeling for the analysis of PET data. Significantly, the drugs whose interaction with the lipid molecule more favorably possessed, in general, a higher nonspecific binding value, whereas for the drugs taken in consideration in this study, the water-octanol partition coefficient, log P, did not show good predictive power of the nonspecific binding. This study also illustrates how ab initio chemical methods may offer meaningful and unbiased insights for the understanding of the underlying chemical mechanisms in biological systems. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] Synthesis and preliminary in vivo evaluation of 4-[18F]fluoro- N -{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide, a potential PET radioligand for the 5-HT1A receptorJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 9 2004M. Vandecapelle Abstract 4-Fluoro- N -{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide is a full 5-HT1A agonist with high affinity (pKi=9.3), selectivity and a c log P of 3.045. The corresponding PET radioligand 4-[18F]fluoro- N -{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor. The fluorinating agent K[18F]F/Kryptofix 2.2.2 was both dried (9 min, 700 W) and incorporated in the precursor (5 min, 700 W) using a commercially available microwave oven. In a total synthesis time of 60 min, an overall radiochemical yield of 18% (SD=5, n=7, EOS) was obtained. Radiochemical purity was always higher than 99% and specific activity always higher than 81.4 GBq/µmol (2.2 Ci/µmol). Initial brain uptake in mice was 2.19% ID (5.47% ID/g, 2 min) but decreased rapidly (0.17% ID, 0.45% ID/g (60 min)). During the first 20 min p.i., radioactivity concentration of the brain was significantly higher than that of blood demonstrating good brain entry of the tracer. Copyright © 2004 John Wiley & Sons, Ltd. [source] General linearized biexponential model for QSAR data showing bilinear-type distributionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2005Peter Buchwald Abstract A major impediment of many QSAR-type analyses is that the data show a maximum or minimum and can no longer be adequately described by linear functions that provide unrivaled simplicity and usually give good description over more restricted ranges. Here, a general linearized biexponential (LinBiExp) model is proposed that can adequately describe data showing bilinear-type distribution as a function of not just often-employed lipophilicity descriptors (e.g., log P) but as a function of any descriptor (e.g., molecular volume). Contrary to Hansch-type parabolic models, LinBiExp allows the natural extension of linear models and fitting of asymmetrical data. It is also more general and intuitive than Kubinyi's model as it has a more natural functional form. It was obtained by a differential equation-based approach starting from very general assumptions that cover both static equilibriums and first-order kinetic processes and that involve abstract processes through which the concentration of the compound of interest in an assumed "effect" compartment is connected to its "external" concentration. Physicochemical aspects placing LinBiExp within the framework of linear free energy relationship (LFER) approaches are presented together with illustrative applications in various fields such as toxicity, antimicrobial activity, anticholinergic activity, and glucocorticoid receptor binding. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2355-2379, 2005 [source] Analyses of the partition coefficient, log P, using ab initio MO parameter and accessible surface area of solute moleculesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2004Hiroshi Chuman Abstract To analyze the log Psol/w values (sol: n -octanol or chloroform, w: water) in the framework of the molecular orbital (MO) procedure, we selected solute descriptors such as the solvation energy difference between aqueous and organic solvent phases and the "surface" area of solute molecules to which water molecules are accessible. The solvation energy of solute molecules in their minimum free-energy conformation was calculated using the ab initio self-consistent reaction field-MO method with the conductor-like screening model. The experimentally measured log Psol/w value of various solutes except for those of amphiprotics was shown to be analyzable reasonably well by the MO model with additional descriptors for the hydrogen-bonding patterns in the solute,solvent interactions. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2681,2697, 2004 [source] High-throughput determination of the free fraction of drugs strongly bound to plasma proteinsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2004Joachim Schuhmacher Abstract Quantification of protein binding of new chemical entities is an important early screening step during drug discovery and is of fundamental interest for the estimation of safety margins during drug development. In this publication, we describe the development of a new high-throughput assay for the determination of the free drug fraction in plasma (fu). The new technique is an enhancement of the previously published erythrocytes partition method. It is based on the distribution of drugs between plasma water, plasma proteins, and solid-supported lipid membranes (Transil®). The execution of protein binding studies by partitioning is dramatically simplified by substituting erythrocytes with commercially available Transil® beads, and makes the method particularly suitable for high-throughput studies. Eight Bayer compounds from different compound classes covering a wide range of lipophilicities (log P,=,1.9,5.6) and fu values (0.018,35%) were selected for validation of the assay. The results obtained by the new method and by either the erythrocytes partitioning technique or more conventional methods (ultrafiltration and equilibrium dialysis) are identical, confirming that the new method produces valid results even for drugs that are strongly bound to plasma proteins. Precision and accuracy of the data in the cases of very low and high fu values are comparable, indicating that the method is especially suited for highly lipophilic drugs that tend to adsorb to surfaces compared with other methods, like ultrafiltration or equilibrium dialysis, that may produce biased data. The method is also useful for the determination of binding parameters and the pH dependence of fu. In summary, this assay is well suited for high-throughput determination of protein binding during drug discovery and for extended protein binding studies during drug development. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 816,830, 2004 [source] QSAR analysis of interstudy variable skin permeability based on the "latent membrane permeability" conceptJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2003Shin-Ichi Fujiwara Abstract A number of QSAR models for skin permeability have been proposed, but these models lack consistency due to interspecies and interlaboratory differences. This study was initiated to extract an essential QSAR from the multiplicity of data sets of skin permeability by using a novel statistical approach. Ten data sets were collected from the literature, which include a total of 111 permeability coefficients in human, hairless mouse, or hairless rat skin for 94 structurally diverse compounds. Following a Potts and Guy's approach, the octanol/water partition coefficient and molecular weight were chosen as molecular descriptors. All of the data sets were analyzed simultaneously, assuming that all of the sets share a latent, common factor as far as the structure/permeability relationship is concerned. Despite the fact that the degree-of-freedom for the present analysis was limited compared with that for individual regression analyses, the determination coefficients (R2) were high enough for all the 10 data sets, with an average R2 of 0.815 (average R2,=,0.825 for individual analyses). Thus, skin permeability of compounds can be well explained from the log P and M.W., where the ratio of the contribution to skin permeability was approximately 1:1. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1939,1946, 2003 [source] Hydrophobic ion pairing of isoniazid using a prodrug approachJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2002Huiyu Zhou Abstract Inhalation therapy for infectious lung diseases, such as tuberculosis, is currently being explored, with microspheres being used to target alveolar macrophages. One method of drug encapsulation into polymeric microspheres to form hydrophobic ion-paired (HIP) complexes, and then coprecipitate the complex and polymer using supercritical fluid methodology. For the potent antituberculosis drug, isoniazid (isonicotinic acid hydrazide, INH), to be used in this fashion, it was modified into an ionizable form suitable for HIP. The charged prodrug, sodium isoniazid methanesulfonate (Na,INHMS), was then ion paired with hydrophobic cations, such as alkyltrimethylammonium or tetraalkylammonium. The logarithms of the apparent partition coefficients (log P,) of various HIP complexes of INHMS display a roughly linear relationship with the numbers of carbon atoms in the organic counterions. The water solubility of the tetraheptylammonium,INHMS complex is about 220-fold lower than that of Na,INHMS, while the solubility in dichloromethane exceeds 10 mg/mL, which is sufficient for microencapsulation of the drug into poly(lactide) microspheres. The actual logarithm of the dichloromethane/water partition coefficient (log P) for tetraheptylammonium,INHMS is 1.55, compared to a value of ,,1.8 for the sodium salt of INHMS. The dissolution kinetics of the tetraheptylammonium,INHMS complex in 0.9% aqueous solutions of NaCl was also investigated. Dissolution of tetraheptylammonium,INHMS exhibited a first-order time constant of about 0.28 min,1, followed by a slower reverse ion exchange process to form Na,INHMS. The half-life of this HIP complex is on the order of 30 min, making the enhanced transport of the drug across biological barriers possible. This work represents the first use of a prodrug approach to introduce functionality that would allow HIP complex formation for a neutral molecule. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1502,1511, 2002 [source] Ester prodrugs of morphine improve transdermal drug delivery: a mechanistic studyJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2007Jhi-Joung Wang Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K,). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and ,75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, ,-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation. [source] Discriminant analysis as a tool to identify compounds with potential as transdermal enhancersJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2005W. J. Pugh Structure-activity relationships were sought for 73 enhancers of hydrocortisone permeation from propylene glycol across hairless mouse skin. Enhancers had chain lengths (CC) from 0 to 16 carbon atoms, 1 to 8 H-bonding atoms (HB), molecular weight 60 to 450, log P (calculated) ,1.7 to 9.7 and log S (calculated) ,7.8 to 0.7. These predictive properties were chosen because of their ready availability. Enhancement ratio (ER) was defined as hydrocortisone transferred after 24 h relative to control. Values for the ER ranged from 0.2 to 25.3. Multiple regression analysis failed to predict activity; ER values for the ,good' enhancers (ER>10) were underestimated. Simple guidelines suggested that high ER was associated with CC>12 and HB 2,5. This was refined by multivariate analysis to identify significant predictors. Discriminant analysis using CC, HB, and molecular weight correctly assigned 11 of the 12 ,good' enhancers (92%). The incorrectly assigned compound was a known, idiosyncratic Br compound. Seventeen of the 61 ,poor' enhancers (28%) were incorrectly assigned but four could be considered marginal (ER>8). The success of this simple approach in identifying potent enhancers suggested its potential in predicting novel enhancer activity. [source] Skin Permeation of Testosterone and its Ester Derivatives in RatsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2000MI-KYEONG KIM To establish the optimum conditions for improving the transdermal delivery of testosterone, we studied the relationship between the lipophilicity of testosterone ester derivatives and the rat skin permeation rate of testosterone. We performed a rat skin permeation study of testosterone and its commercially available ester derivatives, testosterone hemisuccinate, testosterone propionate and testosterone-17,-cypionate, using an ethanol/water co-solvent system. The aqueous solubility and rat skin permeation rate of each drug, saturated in various compositions of an ethanol/water system, was determined at 37°C. The aqueous solubility of testosterone and its ester derivatives increased exponentially as the volume fraction of ethanol increased up to 100% (v/v). The stability of testosterone propionate in both the skin homogenate and the extract was investigated to observe the enzymatic degradation during the skin permeation process. Testosterone propionate was found to be stable in the isotonic buffer solution and in the epidermis-side extract for 10 h at 37°C. However, in the skin homogenate and the dermis-side extract testosterone propionate rapidly degraded producing testosterone, implying that testosterone propionate rapidly degraded to testosterone during the skin permeation process. The steady-state permeation rates of testosterone in the ethanol/water systems increased exponentially as the volume fraction of ethanol increased, reaching the maximum value (2.69 ± 0.69 ,g cm,2 h,1) at 70% (v/v) ethanol in water, and then decreasing with further increases in the ethanol volume fraction. However, in the skin permeation study with testosterone esters saturated in 70% (v/v) ethanol in water system, testosterone esters were hardly detected in the receptor solution, probably due to the rapid degradation to testosterone during the skin permeation process. Moreover, a parabolic relationship was observed between the permeation rate of testosterone and the log P values of ester derivatives. Maximum flux was achieved at a log P value of around 3 which corresponded to that of testosterone (log P = 3.4). The results showed that the skin permeation rate of testosterone and its ester derivatives was maximized when these compounds were saturated in a 70% ethanolic solution. It was also found that a log P value of around 3 is suitable for the skin permeation of testosterone related compounds. [source] Preparation of novel acrylamide-based thermoresponsive polymer analogues and their application as thermoresponsive chromatographic matricesJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 16 2008Yoshikatsu Akiyama Abstract New thermoresponsive polymers based on poly(N -(N, -alkylcarbamido)propyl methacrylamide) analogues were designed with increased hydrophobic content to facilitate temperature-dependent chromatographic separations of peptides and proteins from aqueous mobile phases. These polymer solution exhibited a lower critical solution temperature (LCST) when the alkyl group is methyl, ethyl, isopropyl, propyl, butyl, and isobutyl. However, larger alkyl groups such as hexyl and phenyl were not soluble in aqueous solutions at any temperature. Phase transition temperatures were lower for larger alkyl groups and increased with decreasing polymer molecular weight and concentration in solution. LCST dependence on polymer molecular weight and concentration is more significant compared with well-studied poly(N -isopropylacrylamide) (PIPAAm). Partition coefficient (log P) values for N -(N, -butylcarbamide)propylmethacrylamide and N -(N, -isobutylcarbamide)propyl methacrylamide (iBuCPMA) monomers are larger than that for IPAAm monomer, suggesting higher hydrophobicity than IPAAm. Chromatographic evaluation of poly(N -(N, -isobutylcarbamide)propyl methacrylamide) (PiBuCPMA) grafted silica particles in aqueous separations revealed larger k, values for peptides, insulin, insulin chain B, and angiotensin I than PIPAAm-grafted silica beads. In particular, k, values for insulin obtained from PiBuCPMA-grafted silica separations were much larger than those from PIPAAm-grafted surface separations, indicating that PiBuCPMA should be more hydrophobic than PIPAAm. These results support the introduction of alkylcarbamido groups to efficiently increase thermoresponsive polymer hydrophobicity of poly(N -alkylacrylamides) and poly(N -alkylmethacrylamides). Consequently, poly(N -(N, -alkylcarbamido)propyl methacrylamide) analogues such as PiBuCPMA and poly(N -(N, -alkylcarbamido)alkylmehacrylamide) are new thermoresponsive polymers with appropriate hydrophobic partitioning properties for protein and peptide separations in aqueous media, depending on selection of their alkyl groups. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5471,5482, 2008 [source] Hydrophobicity-aided potentiometric detection of catecholamines, beta-agonists, and beta-blockers in a mixed-solvent capillary electrophoresis systemJOURNAL OF SEPARATION SCIENCE, JSS, Issue 1 2009Grzegorz Bazylak Abstract A series of cationic drug-like substances with distinct basicity, hydrogen-bonding ability, and hydrophobicity, including three catecholamines, two beta-agonists, and thirteen beta-blockers, was successfully detected in a capillary electrophoresis system using an end-capillary coupled potentiometric sensor consisting of a PVC-based liquid membrane deposited directly on a 100 ,m diameter copper rod. The electrophoretic separation was performed on a 72 cm×75 ,m id uncoated fused-silica capillary with an acidic background electrolyte containing phosphoric acid in a water,acetonitrile mixture, pH* 2.8. Samples were injected electrokinetically at 5.0 kV for 10 s and a running voltage of 19.5 kV was applied. Excluding the bufuralol/practolol pair, baseline separation of all substances was achieved in the developed CE system within 9 minutes. A linear relationship (R2 0.8752) between the sensitivity of the applied potentiometric detector and the parameter log P characterising the hydrophobicity of the analytes was demonstrated. The best observable limits of detection (LODs) were obtained for the highly hydrophobic substances, i. e. bufuralol (8.10×10,8 M injected concentration, S/N = 3), propranolol, alprenolol, and clenbuterol (ca. 1.10×10,7 M). In the case of hydrophilic catecholamines and carbuterol their LODs with potentiometric detection were lowered by a factor of almost one thousand, reaching a value of 6.6×10,5 M. [source] Performance of electrospun nanofibers for SPE of drugs from aqueous solutionsJOURNAL OF SEPARATION SCIENCE, JSS, Issue 18 2008Xue-jun Kang Abstract A novel extraction technique was reported. The solid phase material, nanofiber, was prepared by electrospinning using polystyrene. Twenty different drugs (10 ,g/L in water) were extracted using 1 mg of nanofibers within 5 min. The analytes can be desorpted from the fibers with 50 ,L of the methanol and then monitored by LC coupled to a UV detector. Packed-fiber SPE (PFSPE) provide high recoveries (>50%) for some relatively non-polar drugs (log P >1.5) (n -octanol-to-water partition ratio), and relatively low recoveries (9.9,39.8%) for the drugs within the log P window below 1. Experimental optimization of the technique has been carried out using seven representative drugs, edaravone, cinchonine, quinine, voriconazole, chlordiazepoxide, verapamil, and rutonding. Except for edaravone, the maximum yields of seven drugs (0.2 ,g/L) from water samples were approximately 100%, and were 33.7,88.2% from human plasma. The advantageous aspect of the technique encompasses high throughput, high sensitivity, simplicity, low cost, and green chemistry. [source] Cellular response mechanisms in Pseudomonas aeruginosa PseA during growth in organic solventsLETTERS IN APPLIED MICROBIOLOGY, Issue 3 2009R. Gaur Abstract Aims:, Solvent-tolerant bacteria have emerged as a new class of micro-organisms able to grow at high concentrations of toxic solvents. Such bacteria and their solvent-stable enzymes are perceived to be useful for biotransformations in nonaqueous media. In the present study, the solvent-responsive features of a lipase,producing, solvent-tolerant strain Pseudomonas aeruginosa PseA have been investigated to understand the cellular mechanisms followed under solvent-rich conditions. Methods and Results:, The solvents, cyclohexane and tetradecane with differing log P -values (3·2 and 7·6 respectively), have been used as model systems. Effect of solvents on (i) the cell morphology and structure (ii) surface hydrophobicity and (iii) permeability of cell membrane have been examined using transmission electron microscopy, atomic force microscopy and other biochemical techniques. The results show that (i) less hydrophobic (low log P -value) solvent cyclohexane alters the cell membrane integrity and (ii) cells adapt to organic solvents by changing morphology, size, permeability and surface hydrophobicity. However, no such changes were observed in the cells grown in tetradecane. Conclusions:, It may be concluded that P. aeruginosa PseA responds differently to solvents of different hydrophobicities. Bacterial cell membrane is more permeable to less hydrophobic solvents that eventually accumulate in the cytoplasm, while highly hydrophobic solvents have lesser tendency to access the membrane. Significance and Impact of the Study:, To the best of our knowledge, these are first time observations that show that way of bacterial solvent adaptability depends on nature of solvent. Difference in cellular responses towards solvents of varying log P -values (hydrophobicity) might prove useful to search for a suitable solvent for carrying out whole-cell biocatalysis. [source] AGB variables and the Mira period,luminosity relationMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 1 2008Patricia A. Whitelock ABSTRACT Published data for large-amplitude asymptotic giant branch variables in the Large Magellanic Cloud (LMC) are re-analysed to establish the constants for an infrared (K) period,luminosity relation of the form MK=,[log P, 2.38]+,. A slope of ,=,3.51 ± 0.20 and a zero-point of ,=,7.15 ± 0.06 are found for oxygen-rich Miras (if a distance modulus of 18.39 ± 0.05 is used for the LMC). Assuming this slope is applicable to Galactic Miras we discuss the zero-point for these stars using the revised Hipparcos parallaxes together with published very long baseline interferometry (VLBI) parallaxes for OH masers and Miras in globular clusters. These result in a mean zero-point of ,=,7.25 ± 0.07 for O-rich Galactic Miras. The zero-point for Miras in the Galactic bulge is not significantly different from this value. Carbon-rich stars are also discussed and provide results that are consistent with the above numbers, but with higher uncertainties. Within the uncertainties there is no evidence for a significant difference between the period,luminosity relation zero-points for systems with different metallicity. [source] Selecting the right compounds for screening: use of surface-area parametersPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 3 2002Colin M Tice Abstract Polar surface area, total surface area and percentage surface area have been calculated from three-dimensional structures of 88 post-emergence herbicides, 93 pre-emergence herbicides and 237 insecticides. Preferred ranges of values of these parameters were identified. Since the compounds in the training sets are used on a wide variety of species and target sites with various application modes, the parameter ranges are necessarily broad. The utility of the surface-area parameter ranges in selection of compounds for agrochemical screening was compared with the use of ranges of the Lipinski Rule of 5 parameters: molecular mass, calculated log P, number of hydrogen-bond donors and number of hydrogen-bond acceptors. The more computationally intensive surface-area parameters did not offer any obvious advantage over the Lipinski Rule of 5 parameters. © 2002 Society of Chemical Industry [source] Estimating the lipophilicity of a number of 2-amino-1-cyclohexanol derivatives exhibiting anticonvulsant activity ,BIOMEDICAL CHROMATOGRAPHY, Issue 5 2009bieta P Abstract The lipophilicity of a number of N -acyl derivatives of trans - or cis -: racemic, (1R,2R)- or (1S,2S)-aminocyclohexanol (1,13) exhibiting anticonvulsant activity was investigated. Their lipophilicity (Rm0) was determined using reversed-phase thin-layer chromatography (RP-TLC) with mixtures of methanol and water as mobile phases. The partition coefficients of compounds 1,13 (log P) were also calculated using two computer programs (Pallas and Chem DU) and compared with Rm0. Copyright © 2009 John Wiley & Sons, Ltd. [source] Determination of lipophilicity of , -(4-phenylpiperazine) derivatives of N -benzylamides using chromatographic and computational methodsBIOMEDICAL CHROMATOGRAPHY, Issue 4 2008Marek Bajda Abstract This paper describes the evaluation of lipophilicity of ,- (4-phenylpiperazine) derivatives of N -benzylamides. We employed reversed-phase thin-layer chromatography (RP-TLC) and reversed-phase high performance liquid chromatography (RP-HPLC) as experimental methods, using mixtures of acetonitrile and water as the mobile phases with addition of 0.1%TFA in the HPLC experiments. Retention parameters (RM) and capacity factors (log k) determined by applying these methods were linearly dependent on the acetonitrile concentration and enabled us to estimate the relative lipophilicity factors: RM0 and log k0. These factors were compared with the calculated partition coefficients C log P obtained using several software packages. The results indicate that both experimental methods (RP-TLC and RP-HPLC) yielded similar results, and these methods enable determining the lipophilicity of ,- (4-phenylpiperazine) derivatives of N -benzylamides. Significant correlations were found between log P values calculated by Pallas, ALOGPS and C log P Chem3D programs and the experimental data. Copyright © 2007 John Wiley & Sons, Ltd. [source] The effect of stationary phase on lipophilicity determination of , -blockers using reverse-phase chromatographic systemsBIOMEDICAL CHROMATOGRAPHY, Issue 10 2005Tomasz Welerowicz Abstract Evaluation of lipophilicity parameters for basic compounds using different chromatographic stationary phases is presented. An HPLC method for determination of lipophilic molecule,stationary phase interactions was based on gradient analysis. Differences in correlation between the lipophilicity of compounds and experimental chromatographic results obtained in pseudo-membrane systems showed a strong influence of stationary phase structure and physico-chemical properties. , -Blocker drugs with varying lipophilicity and bio-activity were chosen as test compounds. The stationary phases used for the study were monolithic rod-structure C18 and silica gel octadecyl phase SG-C18 as reference material. The second group was silica gel-based polar-embedded alkylamide and cholesterolic phases. The mobile phase was composed of acetonitrile or methanol with ammonium acetate, and a linear gradient of methanol and acetonitrile in mobile phase was performed. A linear correlation of plots of log kg = f(log P) was observed, especially for polar-embedded phases, and this allowed log PHPLC to be calculated. The behavior of stationary phases in methanol and acetonitrile buffer showed differences between obtained log PHPLC values. Copyright © 2005 John Wiley & Sons, Ltd. [source] Characteristics of Immobilized Lipase on Hydrophobic Superparamagnetic Microspheres To Catalyze EsterificationBIOTECHNOLOGY PROGRESS, Issue 2 2004Zheng Guo A novel immobilized lipase (from Candida rugosa) on hydrophobic and superparamagnetic microspheres was prepared and used as a biocatalyst to catalyze esterification reactions in diverse solvents and reaction systems. The results showed that the immobilized lipase had over 2-fold higher activities in higher log P value solvents. An exponential increase of lipase activity against log P of two miscible solvent mixtures was observed for the first time. Both free and immobilized lipase achieved its maximum activity at the range of water activity ( aw) 0.5,0.8 or higher. At aw 0.6, the immobilized lipase exhibited markedly higher activities in heptane and a solvent-free system than did the native lipase. In multicompetitive reactions, the alcohol specificity of the lipase showed a strong chain-length dependency, and the immobilized enzyme exhibited more preference for a longer-chain alcohol, which is different from previous reports. The immobilized lipase showed higher specificities for butyric acid and the medium-chain-length fatty acids (C8,C12). Then, the immobilized lipase was extended to solvent-free synthesis of glycerides from glycerol and fatty acids. Recovered by magnetic separation, the immobilized lipase exhibited good reusability in repeated batch reaction, indicating its promising feature for biotechnology application. [source] Strategic Selection of Hyperthermophilic Esterases for Resolution of 2-Arylpropionic EstersBIOTECHNOLOGY PROGRESS, Issue 5 2003Amitabh C. Sehgal Homologues to Carboxylesterase NP and Candida rugosa lipase, used for the chiral separation of racemic mixtures of 2-arylpropionic methyl esters, were identified by BLAST searches of available genome sequences for hyperthermophilic microorganisms. Two potential candidates were identified: a putative lysophospholipase from Pyrococcus furiosus (Pfu-LPL) and a carboxylesterase from Sulfolobussolfataricus P1 (Sso-EST1). Although both enzymes showed hydrolytic preference toward the (S) methyl ester, only Sso-EST1 yielded highly optically pure (S) naproxen (%eep , 90) and was thus further investigated. Changes in pH or reaction time showed little improvement in %eep or E values with Sso-EST1. However, the addition of 25% methanol resulted in a 25% increase in E. The effect of various cosolvents on the enantiomeric ratio showed no correlation with the log P or dielectric constant values of the solvent. However, an inverse relationship between E and the denaturation capacity (DC) of the water miscible cosolvents was observed. This was attributed to an increase in enzyme flexibility with increasing solvent DC values leading to a concomitant reduction in the resolving power of Sso-EST1. The results here show that although bioinformatics tools can be used to select candidate biocatalysts for chiral resolution of 2-arylpropionic esters, biochemical characterization is needed to definitively determine functional characteristics. [source] | |||||||||||||||||||