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Water Partition Coefficient (water + partition_coefficient)
Selected AbstractsDetermination of physicochemical properties of tetrabromobisphenol AENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2008Hidetoshi Kuramochi Abstract Aqueous solubility (Sw), 1-octanol/water partition coefficient (KOW), and vapor pressure of the nonionic form of 2,2,,6,6,-tetrabromo-4,4,-isopropylidenediphenol (tetrabromobisphenol A or TBBP-A) were measured. From this, enthalpies of solution and vaporization were estimated. Furthermore, enthalpy of fusion and melting point were measured to estimate subcooled liquid vapor pressure, the infinite dilution activity coefficient, and Henry's law constant. Since TBBP-A is expected to exit in both ionic and nonionic forms at near neutral pH, pH effects on physicochemical properties were also examined. Because of the ionization of TBBP-A, Sw increased by five orders of magnitude, while KOW decreased by eight orders of magnitude. Furthermore, an analytical model based on mass balance and dissociation of TBBP-A was applied to represent the pH dependence. [source] Application of ALOGPS to predict 1-octanol/water distribution coefficients, logP, and logD, of AstraZeneca in-house databaseJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2004Igor V. Tetko Abstract The ALOGPS 2.1 was developed to predict 1-octanol/water partition coefficients, logP, and aqueous solubility of neutral compounds. An exclusive feature of this program is its ability to incorporate new user-provided data by means of self-learning properties of Associative Neural Networks. Using this feature, it calculated a similar performance, RMSE,=,0.7 and mean average error 0.5, for 2569 neutral logP, and 8122 pH-dependent logD7.4, distribution coefficients from the AstraZeneca "in-house" database. The high performance of the program for the logD7.4 prediction looks surprising, because this property also depends on ionization constants pKa. Therefore, logD7.4 is considered to be more difficult to predict than its neutral analog. We explain and illustrate this result and, moreover, discuss a possible application of the approach to calculate other pharmacokinetic and biological activities of chemicals important for drug development. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:3103,3110, 2004 [source] Bioconcentration of persistent organic pollutants in four species of marine phytoplanktonENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2005Antje Gerofke Abstract The uptake of polychlorinated biphenyls (PCBs) was studied in four species of marine algae. A novel experimental system to establish and maintain constant dissolved concentrations of PCBs was employed. Headspace sampling was used to verify that the freely dissolved concentrations remained constant with time. The headspace analysis also allowed sorption to dissolved organic carbon (DOC) to be quantified for all but the most lipophilic PCB congeners. Equilibration with the dissolved phase was rapid for three of the four algae species (<1 d for the majority of congeners). Organic carbon,normalized algae/water partition coefficients (KAlgW) were similar for three of the four species, but were lower by a factor of 10 to 20 for Phaeodactylum tricornutum. The KAlgW values of the first three species were similar to the octanol/water partition coefficient (KOW) for those PCB congeners for which DOC sorption could be quantified. These KAlgW values also agreed well with organic carbon,normalized bioconcentration factors for PCBs in suspended particulate matter (BCFSPM) sampled in Baltic Sea surface water during the summer. [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] Sorption of polycyclic aromatic hydrocarbons into liposomes (artificial cell membranes) and the effects of dissolved natural organic matterLAKES & RESERVOIRS: RESEARCH AND MANAGEMENT, Issue 4 2002Yoshihisa Shimizu Abstract Dissolved natural organic matter (NOM) occurs widely in the aquatic environment and affects the fate of microorganic pollutants (e.g. intake, accumulation, movement, degradation, toxicity). The effect of NOM on the intake into biota (living cells) is very important. In the present study, the effects of coexisting NOM on the intake of microorganic pollutants into aquatic biota were experimentally evaluated. The NOM was concentrated from Lake Biwa water using a reverse osmosis filtration membrane. Two polycyclic aromatic hydrocarbons (PAH; pyrene and phenanthrene) were used as representative microorganic pollutants. Liposomes were synthesized in the laboratory to simulate living cell membranes and were used to investigate the intake of microorganic pollutants into aquatic biota. The experimental results (PAH onto NOM, NOM into liposomes, and PAH into liposomes) indicated that the sorption of PAH into liposomes was suppressed, apparently by PAH binding with NOM in the aqueous phase. This suggests that the accumulation and/or toxicity of microorganic pollutants can be retarded by NOM in the aqueous environment. Moreover, the experimental results indicated that sorption into liposomes (the liposome/water sorption coefficient, Klipw) could be a better parameter for estimating the intake of microorganic pollutants into aquatic biota than the n-octanol/water partition coefficient (Kow) in the aqueous environment. [source] Use of affinity capillary electrophoresis for characterizing pharmaceutical colloidal vehicle systems thermodynamicallyBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7-8 2001Neubert Reinhard Abstract This review offers a detailed discussion of the interaction between pharmaceutical compounds and vehicles using the affinity capillary electrophoresis and the microemulsion electrokinetic chromatography. Partition coefficients of drugs were calculated between a micelle and an aqueous phases from the measurement of the migration time, provided the critical micelle concentration and the phase ratio are known. Thermodynamic quantities such as enthalpy and entropy changes of micellar solubilization were calculated from the temperature dependence of the partition coefficients. Partial specific volumes were measured using dynamic light scattering. The logarithm of the partition coefficients and the capacity factor in the micellar system were correlated with the logarithm of the n-octanol/water partition coefficients. Copyright © 2001 John Wiley & Sons, Ltd. [source] Rapidly profiling blood,brain barrier penetration with liposome EKCELECTROPHORESIS, Issue 14 2007Yongjun Wang Abstract This report intended to study the potential of liposome EKC (LEKC) as a convenient and high-throughput screening tool to assess drug penetration across the blood,brain barrier (BBB). The retention factors (k) of 24 structurally diverse compounds were determined with LEKC and vesicle EKC (VEKC), respectively. Principal component analysis of the steady-state concentrations ratio of compounds in the brain and in the blood expressed as log,BB, log,kLEKC, log,kVEKC, and other lipophilic descriptors including octanol/water partition coefficient (Clog,P), octanol/water distribution coefficients (log,D7.4), and polar surface area (PSA), showed the maximum similarity of partitioning processes in LEKC to drug penetration across the BBB. Furthermore, the log,BB were correlated with the above five lipophilic descriptors, and the results showed that log,kLEKC gave the better correlation coefficient (r2,=,0.811, p <0.0001) than those of log,D7.4, Clog,P, PSA, and log,kVEKC (r2,=,0.730, 0.672, 0.627, and 0.620, p <0.0001). This is the first report of the use of LEKC as a promising rapid tool to profile drug penetration across the BBB. [source] The sorptive capacity of animal proteinENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2007Adrian M.H. deBruyn Abstract Partition coefficients that are used to predict concentrations of hydrophobic organic chemicals in biota (e.g., the bioconcentration factor) often assume that the sorptive capacity of an organism or tissue is adequately represented by its lipid content. In lean organisms and tissues, however, theory suggests that partitioning may be strongly influenced by the sorptive capacity of nonlipid materials, such as protein. Little is known about the sorptive capacity of proteins for hydrophobic organic chemicals, and methods to include proteins in bioaccumulation models do not exist. Here, we present a compilation and meta-analysis of published data to estimate the relative sorptive capacities of animal proteins and lipids for neutral organic chemicals. We found that the estimated sorptive capacity of protein in solid animal tissues ranged from around 1 to 10% that of lipid for compounds with a log octanol/water partition coefficient (KOW) of greater than two. The sorptive capacity of blood protein (albumin) appeared to be substantially higher than this, especially for low- KOW chemicals. For modeling purposes, we recommend estimating the sorptive capacity of animal protein as 5% that of lipid. According to this estimate, the sorptive capacity of an animal or tissue will be dominated by the contribution from protein if the lipid content makes up less than 5% of the dry-weight organic content. In such situations, a consideration of the sorptive capacity of nonlipid constituents, such as protein, will permit more accurate predictions of chemical accumulation and distribution. [source] Biomagnification and polychlorinated biphenyl congener distribution in an aquatic predator-prey, host-parasite systemENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 5 2007Maria E. Persson Abstract Biomagnification and polychlorinated biphenyl (PCB) congener distribution was examined in a predator-prey, hostparasite system, in which Atlantic salmon (Salmo salar) preyed upon sprat (Sprattus sprattus). Eubothrium crassum was an intestinal parasite in salmon that also "preyed upon" sprat, because the parasites gained access to foodstuffs via the host (salmon) gut. Salmon contained significantly higher concentrations of total PCBs compared to both parasites and prey (sprat), but no difference in PCB concentration was found between sprat and E. crassum. Salmon biomagnified several PCB congeners from their diet (sprat), whereas parasites did not, despite the fact that both salmon and their parasites ingested the same prey. Differences in nutrient uptake mechanisms between the host and their parasites, in addition to the lack of a gastrointestinal tract in the cestode, may explain the lack of biomagnification in E. crassum. No difference was found in PCB congener distribution between parasites, salmon, and sprat, and none of the animal types showed a preference for accumulating more or less lipophilic congeners (congeners with a high or low octanol/water partition coefficient [KOW]). Biomagnification factors for individual congeners in salmon did not increase with KOW; rather, they were constant, as shown by a linear relationship for congener concentration in prey and predator. [source] Bioconcentration of persistent organic pollutants in four species of marine phytoplanktonENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2005Antje Gerofke Abstract The uptake of polychlorinated biphenyls (PCBs) was studied in four species of marine algae. A novel experimental system to establish and maintain constant dissolved concentrations of PCBs was employed. Headspace sampling was used to verify that the freely dissolved concentrations remained constant with time. The headspace analysis also allowed sorption to dissolved organic carbon (DOC) to be quantified for all but the most lipophilic PCB congeners. Equilibration with the dissolved phase was rapid for three of the four algae species (<1 d for the majority of congeners). Organic carbon,normalized algae/water partition coefficients (KAlgW) were similar for three of the four species, but were lower by a factor of 10 to 20 for Phaeodactylum tricornutum. The KAlgW values of the first three species were similar to the octanol/water partition coefficient (KOW) for those PCB congeners for which DOC sorption could be quantified. These KAlgW values also agreed well with organic carbon,normalized bioconcentration factors for PCBs in suspended particulate matter (BCFSPM) sampled in Baltic Sea surface water during the summer. [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] 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] Ion-pair Formation as a Strategy to Enhance Topical Delivery of Salicylic AcidJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000STELLA A. MEGWA An in-vitro study was carried out to determine the possibility of improving the efficiency of transdermal delivery of salicylate through human epidermis by ion-pair formers (alkylamines and quaternary ammonium ions). Further, the relationship between the physico-chemical properties of the counter-ions and salicylate flux was examined. It was found that flux can be related to the conductivity associated with the penetrant solution, molecular size of the counter-ion and lipophilicity expressed as either octanol/water partition coefficient of the ion pairs or the carbon chain-length of the counter-ions. Equations have been developed to predict salicylate flux from these physicochemical parameters. [source] QSAR Modeling of a Set of Pyrazinoate Esters as Antituberculosis ProdrugsARCHIV DER PHARMAZIE, Issue 2 2010Joćo P. S. Fernandes Abstract Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (J), calculated n -octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r2 = 0.68, q2 = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave- N -out cross-validation and y -scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents. [source] Herbicidal action of 2-hydroxy-3-alkyl-1,4-naphthoquinonesPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 3 2002Philip J Jewess Abstract The main mode of herbicidal activity of 2-hydroxy-3-alkyl-1,4-naphthoquinones is shown to be inhibition of photosystem II (PSII). The herbicidal and in vitro activities have been measured and correlated with their (Log)octanol/water partition coefficients (Log Ko/w). The length of the 3- n -alkyl substituent for optimal activity differed between herbicidal and in vitro activity. The maximum in vitro activity was given by the nonyl to dodecyl homologues (Log Ko/w between 6.54 and 8.12), whereas herbicidal activity peaked with the n -hexyl compound (Log Ko/w,=,4.95). The effect of chain branching was also investigated using isomeric pentyl analogues substituted at position 3. All exhibited similar levels of in vitro activities but herbicidal activities differed, albeit moderately, with the exception of one analogue that was much less phytotoxic. Other modes of action were also investigated using two representative compounds. They did not show any activity on photosystem I or mitochondrial complex I, or generate toxic oxygen radicals by redox cycling reactions. Only moderate activity was found against mitochondrial complex III from plants, in contrast to much higher corresponding activity using an insect enzyme. © 2002 Society of Chemical Industry [source] Insecticidal 2-hydroxy-3-alkyl-1,4-naphthoquinones: correlation of inhibition of ubiquinol cytochrome c oxidoreductase (complex III) with insecticidal activityPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 3 2002Philip J Jewess Abstract The insecticidal and in vitro activities of four homologous series of 2-hydroxy and acetoxy-3-substituted-1,4-naphthoquinones have been measured and correlated with their (Log) octanol/water partition coefficients (Log Ko/w). In vitro activity against mitochondrial complex III was only exhibited by 2-hydroxy-3-alkyl-1,4-naphthoquinones, indicating that the 2-acetoxy compounds act as pro-insecticides. Good correlation was observed between in vivo activity against the two-spotted spider mite, Tetranychus urticae and inhibition of complex III isolated from blowfly flight muscle. Both hydroxy and acetoxy analogues of individual compounds exhibited similar levels of in vivo activity with optimum activity for analogues with Log Ko/w values of 7,8. In contrast, the acetoxy derivatives showed superior in vivo activity against the tobacco whitefly, Bemisia tabaci. Complex III isolated from whitefly was optimally inhibited by hydroxy analogues with lower Log Ko/w values (6.0,6.5) and was also more sensitive than the blowfly enzyme to all the compounds tested. © 2002 Society of Chemical Industry [source] QSARs for aromatic hydrocarbons at several trophic levelsENVIRONMENTAL TOXICOLOGY, Issue 2 2006Walter Di Marzio Abstract Quantitative structure,activity relationships (QSARs) with aromatic hydrocarbons were obtained. Biological response was measured by acute toxicity of several aquatic trophic levels. The chemicals assayed were benzene, toluene, ethylbenzene, o -xylene, m -xylene, p -xylene, isopropylbenzene, n -propylbenzene, and butylbenzene. Acute toxicity tests were carried out with Scenedesmus quadricauda, as representative of primary producers; Daphnia spinulata, a zooplanctonic cladoceran; Hyalella curvispina, a benthic macroinvertebrate; and Bryconamericus iheringii, an omnivorous native fish. The EC50 or LC50 was calculated from analytical determinations of aromatic hydrocarbons. Nonlinear regression analysis between the logarithm of the octanol,water partition coefficient (log Kow) of each compounds and the toxicity end points was performed. QSARs were positively related to increases in log Kow at all trophic levels. Intertaxonomic differences were found in comparisons of algae with animals and of invertebrates with vertebrates. We observed that these differences were not significant with a log Kow higher than 3 for all organisms. Aromatic hydrocarbons with log Kow values of less than 3 showed different toxicity responses, with algae more resistant than fish and invertebrates. We concluded that this was a result of the narcotic mode of action related to liposolubility and the ability of the compound to reach its target site in the cell. The bioconcentration factor (BCF) achieved to start nonpolar narcosis fell almost 1 order of magnitude below the BCF expected from the log Kow. Predicted critical body residues for nonpolar narcosis ranged between 2 and 1 mM. © 2006 Wiley Periodicals, Inc. Environ Toxicol 21: 118,124, 2006. [source] Persistent or not persistent?ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2009Polychlorinated biphenyls are readily depurated by grizzly bears (Ursus arctos horribilis) Abstract Major pharmacokinetic processes influencing polychlorinated biphenyl (PCB) accumulation in mammals include uptake, biotransformation, respiration, and excretion. We characterized some of the factors underlying PCB accumulation/loss by evaluating PCB concentrations and patterns in pre- and posthibernation grizzly bears (Ursus arctos horribilis) and their prey. The PCB congeners with vicinal meta - and para -chlorine unsubstituted hydrogen positions consistently showed loss both before and during hibernation, supporting the idea of a dominant role for biotransformation. Retention of all other studied congeners relative to that of PCB 194 varied widely (from <1 to 100%) and was highly correlated with log octanol--water partition coefficient (p < 0.0001). A lack of loss for most of these other congeners during hibernation supports the notion that excretion (e.g., fecal or urinary) or lack of uptake during the feeding season underlies their lack of accumulation, because hibernating bears do not eat or excrete. We estimate that grizzly bears retain less than 10% of total PCBs taken up from their diet. Our results suggest that for grizzly bears, depuration of PCBs via biotransformation is important (explaining ,40% of loss), but that nonbiotransformation processes, such as excretion, may be more important (explaining ,60% of loss). These findings, together with the approximately 91% loss of the persistent PCB 153 congener relative to PCB 194 in grizzly bears, raise important questions about how one defines persistence of PCBs in wildlife and may have bearing on the interpretation of food-web biomagnification studies. [source] Influence of soil pH on the sorption of ionizable chemicals: Modeling advancesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2009Antonio Franco Abstract The soil,water distribution coefficient of ionizable chemicals (Kd) depends on the soil acidity, mainly because the pH governs speciation. Using pH-specific Kd values normalized to organic carbon (KOC) from the literature, a method was developed to estimate the KOC of monovalent organic acids and bases. The regression considers pH-dependent speciation and species-specific partition coefficients, calculated from the dissociation constant (pKa) and the octanol,water partition coefficient of the neutral molecule (log Pn). Probably because of the lower pH near the organic colloid,water interface, the optimal pH to model dissociation was lower than the bulk soil pH. The knowledge of the soil pH allows calculation of the fractions of neutral and ionic molecules in the system, thus improving the existing regression for acids. The same approach was not successful with bases, for which the impact of pH on the total sorption is contrasting. In fact, the shortcomings of the model assumptions affect the predictive power for acids and for bases differently. We evaluated accuracy and limitations of the regressions for their use in the environmental fate assessment of ionizable chemicals. [source] Estimation of the soil,water partition coefficient normalized to organic carbon for ionizable organic chemicals,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2008Antonio Franco Abstract The sorption of organic electrolytes to soil was investigated. A dataset consisting of 164 electrolytes, composed of 93 acids, 65 bases, and six amphoters, was collected from literature and databases. The partition coefficient log KOW of the neutral molecule and the dissociation constant pKa were calculated by the software ACD/Labs®. The Henderson-Hasselbalch equation was applied to calculate dissociation. Regressions were developed to predict separately for the neutral and the ionic molecule species the distribution coefficient (Kd) normalized to organic carbon (KOC) from log KOW and pKa. The log KOC of strong acids (pKa < 4) was not correlated to these parameters. The regressions derived for weak acids and bases (undissociated at environmental pH) were similar. The highest sorption was found for strong bases (pKa > 7.5), probably due to electrical interactions. Nonetheless, their log KOC was highly correlated to log KOW. For bases, a nonlinear regression was developed, too. The new regression equations are applicable in the whole pKa range of acids, bases, and amphoters and are useful in particular for relatively strong bases and amphoters, for which no predictive methods specifically have been developed so far. [source] Predicting single and mixture toxicity of petrogenic polycyclic aromatic hydrocarbons to the copepod Oithona davisaeENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2005Carlos Barata Abstract In the present study, the acute toxicity of 10 polycyclic aromatic hydrocarbons (PAH) associated with the Prestige fuel oil spill (Spain, 2002) were evaluated, either as single substances or in mixtures, in adults of the copepod Oithona davisae. All but dimethylphenanthrene had negative effects on O. davisae survival at concentrations below their water solubility, with 48-h median lethal concentrations for naphthalene and pyrene of 56.1 and 0.8 ,mol/L, respectively, making these the least and most toxic compounds. Polycyclic aromatic hydrocarbons had narcotic effects on copepods, as evidenced by the lack of motility at lower concentrations than those causing death. Naphthalene showed the greatest narcotic effects, and phenanthrene showed minor effects. Acute toxicity of the tested PAHs was inversely related (r2 = 0.9) with their octanol,water partition coefficient, thereby confirming the validity of the baseline quantitative structure,activity regression models for predicting the toxicity of PAH compounds in copepod species. When supplied in mixtures, the toxic effect of PAHs was additive. These results indicate that the many PAHs in an oil spill can be considered unambiguous baseline toxicants (class 1) acting additively as nonpolar narcotics in copepods; hence, their individual and combined toxicity can be predicted using their octanol,water partition coefficient. [source] Biomimetic solid-phase microextraction to predict body residues and toxicity of chemicals that act by narcosisENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2002Heather A. Leslie Abstract A biomimetic extraction technique using solid-phase microextraction (SPME) fibers has been developed for the risk assessment of contaminants with a narcotic mode of action. Our goal is to apply this technique in the future for the prediction of total baseline toxicity of environmental water and effluent samples. Validation of this method requires establishing the relationship between contaminant accumulation and toxicity in biota and accumulation in the surrogate solid phase (the SPME fiber coating). For this purpose, we determined the median lethal concentration (LC50) values for Chironomus riparius midge larvae exposed to two halogenated aromatic compounds separately and measured body residues in the exposed larvae. Solid-phase microextraction fibers with an 85-,m polyacrylate (PA) coating served as the surrogate hydrophobic phase, mimicking the uptake of the compounds by midge larvae. The toxicant concentrations in SPME fibers measured directly by gas chromatography/mass spectrometry (GCMS) or calculated from the SPME fiber,water partition coefficient, KSPME, were related to the toxicant concentrations found in midge larvae. Our results demonstrated that the biomimetic SPME method enables the estimation of body residues in biota and prediction of the degree of baseline toxicity of a water medium. [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] An evaluation of mathematical models for predicting skin permeabilityJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2008Guoping Lian Abstract A number of mathematical models have been proposed for predicting skin permeability, mostly empirical and very few are deterministic. Early empirical models use simple lipophilicity parameters. The recent trend is to use more complicated molecular structure descriptors. There has been much debate on which models best predict skin permeability. This article evaluates various mathematical models using a comprehensive experimental dataset of skin permeability for 124 chemical compounds compiled from various sources. Of the seven models compared, the deterministic model of Mitragotri gives the best prediction. The simple quantitative structure permeability relationships (QSPR) model of Potts and Guy gives the second best prediction. The two models have many features in common. Both assume the lipid matrix as the pathway of transdermal permeation. Both use octanol,water partition coefficient and molecular size. Even the mathematical formulae are similar. All other empirical QSPR models that use more complicated molecular structure descriptors fail to provide satisfactory prediction. The molecular structure descriptors in the more complicated QSPR models are empirically related to skin permeation. The mechanism on how these descriptors affect transdermal permeation is not clear. Mathematically it is an ill-defined approach to use many colinearly related parameters rather than fewer independent parameters in multi-linear regression. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:584,598, 2008 [source] Lipophilicity affects the pharmacokinetics and toxicity of local anaesthetic agents administered by caudal blockCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2004Alejandro A Nava-Ocampo Summary 1.,Drugs administered into the epidural space by caudal block are cleared by means of a process potentially affected by the lipophilic character of the compounds. 2.,In the present study, we examined the relationship between the octanol,water partition coefficient (log Poct) and the time to reach the maximum plasma drug concentration (tmax) of lignocaine, bupivacaine and ropivacaine administered by caudal block in paediatric patients. We also examined the relationship between log Poct and the toxicity of these local anaesthetic agents in experimental models. The tmax and toxicity data were obtained from the literature. 3.,Ropivacaine, with a log Poct of 2.9, exhibited a tmax of 61.6 min. The tmax of lignocaine, with a log Poct of 2.4, and bupivacaine, with a log Poct of with 3.4, were approximately 50% shorter than ropivacaine. At log Poct of approximately 3.0, the toxicity of these local anaesthetic agents was substantially increased. The relationship between log Poct and the convulsive effect in dogs was similar to the relationship between log Poct and the lethal dose in sheep. 4.,With local anaesthetic agents, it appears that the relationship between log Poct and drug transfer from the epidural space to the blood stream is parabolic, being the slowest rate of transference at log Poct 3.0. Toxicity, due to plasma availability of these local anaesthetic agents, seems to be increased at log Poct equal or higher than 3.0 secondary to the highest transfer from plasma into the central nervous system. [source] Sampling in the Great Lakes for pharmaceuticals, personal care products, and endocrine-disrupting substances using the passive polar organic chemical integrative samplerENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 4 2010Hongxia Li Abstract The passive polar organic chemical integrative sampler in the pharmaceutical configuration (i.e., pharmaceutical-POCIS) was calibrated for sampling at water temperatures of 5, 15 and 25°C to determine the influence of temperature on chemical-specific sampling rates (RS), thus providing more robust estimates of the time-weighted average concentrations of pharmaceuticals and personal care products (PPCPs) and endocrine-disrupting substances (EDS) in surface water. The effect of water temperature and flow on the RS of these analytes was evaluated in the laboratory with a static system. The loss of the test compounds from water by uptake into POCIS was linear over an 8-d period, and these experimental data yielded RS values in the range of 0.07 to 2.46 L/d across the temperature range for the 30 compounds tested. Water temperature and flow influenced POCIS uptake rates, but these effects were relatively small, which is consistent with the theory for uptake into POCIS samplers. Therefore, under a narrow range of water temperatures and flows, it may not be necessary to adjust the RS for POCIS. Except for acidic drugs and sulfonamide antibiotics, RS values were positively correlated with octanol,water partition coefficients (log KOW) of the test compounds. A linear relationship was also observed between RS and chromatographic retention times on a C18 reversed-phase column. These observations may provide a rapid method for estimating the RS of additional chemicals in the POCIS. The application of the RS to POCIS deployed for one month in Lake Ontario, Canada, during the summers of 2006 and 2008 yielded estimates of PPCP and EDS concentrations that are consistent with conventional concentration measurements of these compounds in Lake Ontario surface water. Environ. Toxicol. Chem. 2010;29:751,762. © 2009 SETAC [source] Assessing exposure of sediment biota to organic contaminants by thin-film solid phase extractionENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2009Lizanne M. Meloche Abstract Differences in bioavailability among sediments are a source of variability and uncertainty in sediment quality assessment. We present three sets of studies designed to test a thin-film solid phase extraction technique for characterizing the bioavailability of organic chemicals in sediments. Laboratory studies with spiked natural sediments reveal highly reproducible thin-film extractions for chemicals with octanol,water partition coefficients between 104.5 and 108.5, with 95% equilibration times between 1 and 600 h. Studies with field-collected sediments illustrate that method detection limits are sufficiently low for field application at contaminated sites. Bioaccumulation studies with clams (Macoma balthica) show excellent correlations between thin-film and animal tissue concentrations. We conclude that thin-film extraction provides an ecologically relevant, fugacity-based measure of chemical exposure that can be expected to improve sediment quality assessments. [source] Field testing of equilibrium passive samplers to determine freely dissolved native polycyclic aromatic hydrocarbon concentrationsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2008Gerard Cornelissen Abstract Equilibrium passive samplers are promising tools to determine freely dissolved aqueous concentrations (CW,free) of hydrophobic organic compounds. Their use in the field, however, remains a challenge. In the present study on native polycyclic aromatic hydrocarbons (PAHs) in Oslo Harbor, Norway, two different passive sampler materials, polyoxymethylene (POM; thickness, 55 ,m [POM-55] and 500 ,m [POM-500]) and polydimethylsiloxane (PDMS; thickness, 200 ,m), were used to determine in the laboratory CW,free in sediment pore water (CPW,free), and the suitability of five passive samplers for determination of CW,free in overlying surface water was tested under field conditions. For laboratory determinations of CPW,free, both POM-55 and PDMS turned out to be suitable. In the field, the shortest equilibrium times (approximately one month) were observed for POM-55 and PDMS (thickness, 28 ,m) coatings on solid-phase microextraction fibers, with PDMS tubing as a good alternative. Low-density polyethylene (thickness, 100 ,m) and POM-500 did not reach equilibrium within 119 d in the field. Realistic values were obtained for dissolved organic carbon,water partition coefficients in the field (approximately one log unit under log KOW), which strengthened the conclusion that equilibrium was established in field-exposed passive samplers. At all four stations, chemical activity ratios between pore water and overlying water were greater than one for all PAHs, indicating that the sediment was a PAH diffusion source and that sediment remediation may be an appropriate treatment for PAH contamination in Oslo Harbor. [source] Estimating metabolic biotransformation rates in fish from laboratory dataENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2008Jon A. Arnot Abstract A method is proposed for estimating metabolic biotransformation rate constants for nonionic organic chemicals from measured laboratory bioconcentration and dietary bioaccumulation data in fish. Data have been selected based on a quality review to reduce uncertainty in the measured values. A kinetic mass balance model is used to estimate rates of chemical uptake and elimination. Biotransformation rate constants are essentially calculated as the difference between two quantities, a measured bio-concentration factor or elimination rate constant, and a model-derived bioconcentration factor or elimination rate constant estimated assuming no biotransformation. Model parameterization exploits key empirical data when they are available and assumes default values when study specific data are unavailable. Uncertainty analyses provide screening level assessments for confidence in the biotransformation rate constant estimates. The uncertainty analyses include the range for 95% of the predicted values and 95% confidence intervals for the calculated biotransformation values. Case studies are provided to illustrate the calculation and uncertainty methods. Biotransformation rate constants calculated by the proposed method are compared with other published estimates for 31 chemicals that range in octanol,water partition coefficients from approximately 101 to 108 and represent over four orders of magnitude in biotransformation potential. The comparison of previously published values with those calculated by the proposed method shows general agreement with 82% of the estimated values falling within a factor of three. [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] | |||||||||||||||||||