Computational Oral Absorption Simulation for Low‐Solubility Compounds

Bile micelles play an important role in oral absorption of low‐solubility compounds. Bile micelles can affect solubility, dissolution rate, and permeability. For the pH–solubility profile in bile micelles, the Henderson–Hasselbalch equation should be modified to take bile‐micelle partition into account. For the dissolution rate, in the Nernst–Brunner equation, the effective diffusion coefficient in bile‐micelle media should be used instead of the monomer diffusion coefficient. The diffusion coefficient of bile micelles is 8‐ to 18‐fold smaller than that of monomer molecules. For permeability, the effective diffusion coefficient in the unstirred water layer adjacent to the epithelial membrane, and the free fraction at the epithelial membrane surface should be taken into account. The importance of these aspects is demonstrated here using several in vivo and clinical oral‐absorption data of low‐solubility model compounds. Using the theoretical equations, the food effect on oral absorption is further discussed.     

Effect of complex formation by taxifolin and naringenin with Cu(i) ions on the distribution of the components of complexes in the octanol–water system

The interaction of two structurally close flavanones: taxifolin and naringenin with copper(I) ions and its effect on the distribution of flavonoids and the corresponding ions in a biphasic system octanol–water have been studied. It has been shown that these polyphenols form complexes with copper ions of different stoichiometric ratio depending on the pH of medium (5.4, 7.4, and 9.0). The interaction of the flavonoids with copper ions leads to an increase in the fraction of polyphenols in the water phase at all pH values examined. The fraction of metal ions in octanol in the presence of both taxifolin and naringenin is maximal in the range of neutral pH values. The parameters obtained in the study, such as the partition coefficient and the coefficient of distribution in a biphasic system octanol–water (logP and logD) form the physicochemical basis necessary for the estimation of the bioavailability of flavonoids and the corresponding metal ions upon their combined consumption.     

Uptake and clearance of PCB congeners in Chamaelea gallina: response of oxidative stress biomarkers

PCB uptake and clearance by clams, Chamaelea gallina, were studied in specially designed flow-through channels. After 8 weeks exposure to 10 ppb Aroclor 1254 in water, clams were depurated for 10 weeks, in the same exposure channel or after transfer to clean systems. Accumulation of the 20 congeners studied depended on its initial abundance and physicochemical properties. A linear relationship was found between log bioconcentration factor and log octanol/water partition coefficient of each form. Clearance of each PCB depended also on its initial load and solubility, being faster in clams transferred to clean systems. Exposure significantly enhanced catalase and 6-P-gluconate dehydrogenase activities, but not other antioxidative enzymes. Superoxide dismutase, low during the exposure phase, increased seven-fold during depuration. Aroclor-treated clams had higher GSH levels than controls, but decreased to 15-35% after 2 days clearance, rose to 150% after 12 days, and declined to low levels by the end of the experience. Biotransformation of PCBs to quinones and redox cycling-promoted oxidative stress might explain the increased antioxidative defenses. The biochemical changes observed at the beginning of clearance could be attributed to clam handling, by adaptation to and recovery from hypoxic/anoxic stress.     

Developmental toxicity evaluation of sodium thioglycolate administered topically to Sprague-Dawley (CD) rats and New Zealand White rabbits

BACKGROUND: Sodium thioglycolate, which has widespread occupational and consumer exposure to women from cosmetics and hair‐care products, was evaluated for developmental toxicity by topical exposure during the embryonic and fetal periods of pregnancy METHODS: Timed‐mated Sprague–Dawley rats (25/group) and New Zealand White (NZW) rabbits (24/group) were exposed to sodium thioglycolate in vehicle (95% ethanol:distilled water, 1:1) by unoccluded topical application on gestational days (GD) 6–19 (rats) or 6–29 (rabbits) for 6 hr/day, at 0, 50, 100, or 200 mg/kg body weight/day (rats) and 0, 10, 15, 25, or 65 mg/kg/day (rabbits). At termination (GD 20 rats; GD 30 rabbits), fetuses were examined for external, visceral, and skeletal malformations and variations. RESULTS: In rats, maternal topical exposure to sodium thioglycolate, at 200 mg/kg/day (the highest dose tested) on GD 6–19, resulted in maternal toxicity, including reduced body weights and weight gain, increased relative water consumption and one death. Treatment‐related increases in feed consumption and changes at the application site occurred at all doses, in the absence of increased body weights or body weight change. Fetal body weights/litter were decreased at 200 mg/kg/day, with no other embryo/fetal toxicity and no treatment‐related teratogenicity in any group. In rabbits, maternal topical exposure to sodium thioglycolate on GD 6–29 resulted in maternal dose‐related toxicity at the dosing site in all groups; no maternal systemic toxicity, embryo/fetal toxicity, or treatment‐related teratogenicity were observed in any group. CONCLUSIONS: A no observed adverse effect level (NOAEL) was not identified for maternal toxicity in either species with the dosages tested. The developmental toxicity NOAEL was 100 mg/kg/day (rats) and ≥65 mg/kg/day (rabbits; the highest dose tested). The clinical relevance of theses study results is uncertain because no data were available for levels, frequency, or duration of exposures in female workers or end users. Birth Defects Research Part B 68:144–161, 2003. © 2003 Wiley‐Liss, Inc.     

Enzymatic Production of Alkyl Esters Through Lipase-Catalyzed Transesterification Reactions in Organic Solvents: Solvent Effects and Prediction Capabilities of Equilibrium Conversions

The solvent effect on the equilibrium position of the transesterification reaction of hexanol with ethyl acetate catalyzed by a lipase has been investigated in a variety of non-polar and polar solvents - and binary mixtures. The results obtained indicate that the solvent effect on the equilibrium conversion is very small as compared to that for the direct esterification reactions.

Equilibrium conversions were then predicted using the equilibrium constant for the reaction obtained from Gibbs free energy of formation information for reactants and products in combination with the UNIFAC activity coefficient model. A solvent independent equilibrium conversion was obtained, which was in good agreement with the observed average value for all solvents. This indicates that UNIFAC provides satisfactory estimates of the activity coefficients but its group contribution structure does not allow the prediction of the small differences in conversion among the solvents examined.

Finally plots of these conversions versus the solvent octanol/water partition coefficient or the solubility of water in the solvent, that provide the correct trend in direct esterification reactions, did not achieve the same for transesterification.     

Schistosoma mansoni: Correlation between lipid partition coefficients and the transintegumental uptake of nonelectrolytes

Comparison of transintegumental membrane permeability and partition coefficients of selected nonelectrolytes attempted to correlate the parameters of lipid solubility and membrane permeation in male and female Schistosoma mansoni. Transintegumental uptakes and octanol:water partition coefficients were determined for 10 nonelectrolytes (acetamide, antipyrine, benzyl alcohol, caffeine, ethanol, ethylene glycol, propylene glycol, sucrose, thiourea, and urea). Linear regression analyses comparing the logarithm of the partition coefficient to the transintegumental uptakes yielded values of R = 0.80 (P < 0.001) for males, R = 0.84 (P < 0.001) for females, and R = 0.82 (P < 0.001) for a combined analysis of males and females. The male and female schistosomes showed no statistically significant differences in correlation of these parameters. The evidence, then, suggests that the multilaminate membrane functions in a way similar to the function of a lipid bilayer with regard to the parameters studied.     

Partition coefficients of quinones and hydroquinones and their relation to biochemical reactivity

Some major effects of ring substituents on the partition coefficients of quinone headgroups are described. Attention is drawn to the large differences in partition coefficients in cyclohexane/water of the two major freely diffusing redox forms, the quinone, Q, and the hydroquinone, QH2. Methoxy substituents cause a marked increase of the cyclohexane/water partition coefficient of the hydroquinone, but this effect is absent in the quinone and is also not seen in measurements in octanol/water. The relation between partition coefficients and biochemical specificity of quinone binding sites is explored.     

Degradation of Mono-Fluorophenols by an Acclimated Activated Sludge

Acclimated activated sludge was examined for its ability to degrade mono-fluorophenols as the sole carbon source in aerobic batch cultures. The acclimated activated sludge degraded fluorophenol efficiently. It degraded 100 mg/l 3-fluoropheno and 4-fluorophenol in 16 h with, respectively, 99.85% and 99.91% fluoride anion release and it degraded 50 mg/l 2-fluorophenol in 15 h with 99.26% fluoride anion release. The aerobic biodegradability of the mono-fluorophenols decreased in the order: 4-fluorophenol > 3-fluorophenol > 2-fluorophenol, resulting mainly from a different octanol/water partition coefficient and different steric parameter of the fluorophenols. The mechanism study revealed that the initial step in the aerobic biodegradation of mono-fluorophenols by the activated sludge was their transformation to fluorocatechol. Following transformation of the fluorophenol to fluorocatechol, ring cleavage by catechol 1, 2-dioxygenases proceeded via an ortho-cleavage pathway, then defluorination occurred.     

Isothiocyanates. A new class of uncouplers.

This paper describes the uncoupling effect of three isothiocyanates: p-bromophenylisothiocyanate, 4,4'-diisothiocyanatebiphenyl and beta-naphtylemthylisothiocyanate on the respiration of Ehrlich-Lettré cells and isolated mitochondria. The isothiocyanates are similar to other uncouplers (such as 2,4-dinitrophenol and carbonyl cyanide p-trifluoromethoxyphenylhydrazone) in that they: 1. stimulate respiration of state 4 mitochondria; 2. stimulate mitochondrial ATPase activity; 3. release the inhibition of mitochondrial respiration by oligomycin and 4. inhibit both mitochondrial respiration and mitochondrial ATPase activity at higher molar concentrations. The incoupling activity of these isothiocyanates correlates well with their biological activity. Maximal activation of a latent mitochondrial ATPase activity of rat liver mitochondria in the presence of p-bromophenylisothiocyanate was found at a concentration of 15 muM. The investigated isothiocyanates differ significantly in their solubility in organic solvents and their chemical reactivity. We assume that the greater the partition coefficient in a series of isothiocyanates grouped according to the increasing value of log P (partition coefficient for the system octanol/water, 25 degrees C), the greater will be their uncoupling activity, but only up to a certain degree. Any further increase of log P will be marked by a decrease of this activity.     

Sol-gel immobilisation of Saccharomyces cerevisiae enhances viability in organic media

The polyhydroxylated silane network of a sol-gel protected immobilised Saccharomyces cerevisiae against the effects of five organic solvents. The viability of immobilised yeast directly correlated with the logarithm of the partition coefficient of the solvent in an octanol/water two phase system increasing the decimal reduction time (D) and reaching the maximum with octanol, the most hydrophobic solvent assayed. The D value increased from 0.16 min for free yeast to 1.9 and to 22 min for immobilised yeast exposed to ethanol and 1-octanol respectively.     

Transdermal Permeation of Kaempferia parviflora Methoxyflavones from Isopropyl Myristate-Based Vehicles

Kaempferia parviflora (K. parviflora) rhizomes have long been used in traditional folk medicines and as general health-promoting agents. Several biological activities of K. parviflora, especially its anti-inflammatory effect, are due to its major constituents, methoxyflavones. However, the oral bioavailability of these methoxyflavones has been shown to be low. The aim of this study was to investigate the permeation behaviors of K. parviflora methoxyflavones from isopropyl myristate (IPM)-based vehicles. We studied the effects of ethanol and propylene glycol (PG) as the hydrophilic, solvent-type vehicles as well as fatty acids as the permeation enhancers. A permeation experiment was performed in vitro, using side-by-side diffusion cells through the full thickness of pig ear skin. The solubility and permeation of methoxyflavones were able to be modified by choice and ratio of vehicles. The ethanol/IPM vehicle was shown to be more effective in enhancing the solubility and permeation of methoxyflavones when compared to the PG/IPM vehicle. Regarding an optimal balance between solubility or affinity to vehicle and skin to vehicle partition coefficient, the ethanol/IPM vehicle in the ratio of 1:9 maximized the flux. Among the investigated fatty acids, oleic acid showed the greatest enhancing effect on the permeation of methoxyflavones, indicating that saturated fatty acids are less effective than unsaturated fatty acids. Long chain fatty acids increased diffusion coefficient parameter and shortened the lag time. The number of carbon atoms and double bonds of fatty acids did not show direct relation to the profile of permeation of methoxyflavones.     

Passive Membrane Penetration of the Serotonin Precursor 5‐Hydroxytryptophan is Controlled by Its Zwitterion

Species‐specific partition coefficients in the octanol/water system were determined for the neurotransmitter serotonin (5‐HT) and its precursor 5‐hydroxytryptophan (5‐HTP). The pH‐independent partition coefficients (p) of the individual microspecies were determined by combination of experimentally measured distribution constants and a custom‐tailored evaluation method, using highly similar auxiliary compounds. Experimental microscopic partition coefficients for triprotic molecules have only been reported before for thyroxine and its derivatives. The parabolic pH‐distribution profile of 5‐HT shows the dominance of the lipophilic non‐charged microspecies, with a log p of 0.66. However, the most lipophilic non‐charged form of 5‐HTP, with a log p of 0.31, has no significant contribution to the distribution coefficient at any pH value. Instead, the less lipophilic zwitterionic protonation isomer dominates the distribution in the pH range 2.10 – 11.11. Although the non‐charged microspecies of 5‐HTP is 151 times more lipophilic than its zwitterionic protonation isomer, the overwhelming dominance of the zwitterionic form ensures that its contribution to the overall lipophilicity exceeds 1320 times that of the non‐charged one. This fact is another counter‐example of the widespread belief that passive diffusion into lipophilic media is predominated by the non‐charged species. The lipophilicity profile of 5‐HT and 5‐HTP is depicted in terms of species‐specific lipophilicities.     

Chemicobiological interactions and the use of partition coefficients in their correlation

Using octanol/water partition coefficients as an operational definition of hydrophobicity, 70 examples are given in which the hydrophobic interactions of organic compounds with themselves (in micelles) with macromolecules or with biological systems can be quantitatively correlated by the expression: log RBR = a log P + b. In this expression RBR is a binding constant or a relative biological response, P is the octanol/water partition coefficient and a and b are constants obtained via the method of least squares. These results are strong support for the utility of log P in the correlation of hydrophobic interactions. They also illustrate the extremely wide range of processes in which hydrophobic bonding plays a critical role.     

A curcumin-diglutaric acid conjugated prodrug with improved water solubility and antinociceptive properties compared to curcumin

In this work, a curcumin-diglutaric acid (CurDG) prodrug was synthesized by conjugation of curcumin with glutaric acid via an ester linkage. The water solubility, partition coefficient, release characteristics, and antinociceptive activity of CurDG were compared to those of curcumin. The aqueous solubility of CurDG (7.48 μg/mL) is significantly greater than that of curcumin (0.068 μg/mL). A study in human plasma showed that the CurDG completely releases curcumin within 2 h, suggesting the ability of CurDG to serve as a prodrug of curcumin. A hot plate test in mice showed the highest antinociceptive effect dose of curcumin at 200 mg/kg p.o., whereas CurDG showed the same effect at an effective dose of 100 mg/kg p.o., indicating that CurDG significantly enhanced the antinociceptive effect compared to curcumin. The enhanced antinociceptive effect of CurDG may be due to improved water solubility and increased oral bioavailability compared to curcumin.     

Synthesis and biological evaluation of novel conjugates of podophyllotoxin and 5-FU as antineoplastic agents

A series of novel conjugates of podophyllotoxin and 5-FU were designed using association strategy and were synthesized by coupling 4′-demethylepipodophyllotoxin with 5-FU-N¹-alkyl amino acid ester. These derivatives have been evaluated for cytotoxicity in vitro against tumour cell lines (HL-60, K562, A-549 and AGS), and their octanol–water partition coefficients (log P) were also determined. As compared with VP-16, most compounds showed superior water solubility, as well as more potent inhibitions against these four tumour cell lines. Compound 21 showed interaction with calf thymus DNA, and it was relatively resistant to metabolism by human plasma.     

Diffusion within egg lecithin bilayers resembles that within soft polymers

An analysis is presented of how the permeability coefficient/octanol:water partition coefficient ratio for 33 different chemical substances crossing egg lecithin bilayers depends on the molecular volume of the substances. From this analysis we conclude that bilayers made from egg lecithin behave as soft polymers in their discrimination between permeants of different sizes and shapes.     

Correlation between lipid partition coefficients and surface permeation inSchistosoma japonicum

Summary Comparison of transintegumental membrane permeability and partition coefficients of selected nonelectrolytes was attempted to correlate the parameters of lipid solubility, hydrophilicity, and membrane permeation in male and female schistosomes (parasites of the portal venous tributaries of man). Surface permation (measured by the triple isotope technique) and octanol/water partition coefficients were determined for 17 compounds (acetamide, aminopyrine, antipyrine, benzyl alcohol, butanol, caffeine, ethanol, ethylene glycol, glycerol, inosine, mannitol, methanol, polyethylene glycol, propylene glycol, sucrose, thiourea, and urea).Linear regression analyses comparing the logarithm of the partition coefficient to transintegumental uptakes indicate a positive correlation in both sexes:R=0.76 (P<0.001) for males, andR=0.77 (P<0.001) for females. Similarly, linear regression analyses comparing hydrogen bond number with the logarithm of tissue uptake index demonstrate a high (negative) correlation in both males (R=–0.85,P<0.001) and females (R=–0.90,P<0.001). The male and female schistosomes showed no statistically significant differences in correlation of these parameters. Surface permeation was the same in male and female schistosomes, suggesting that male-female variations in integumental uptake rates previously observed may be restricted to metabolites which enter by way of a selective carrier system.     

Chelation therapy for methylmercury(II) poisoning. Synthesis and determination of solubility properties of MeHg(II) complexes of thiol and dithiol antidotes

Methylmercury(II) complexes of the most widely studied antidotes for mercury poisoning have been prepared, and both the water solubility and 1-octanol/water partition coefficients determined for these complexes and the L-cysteine complex. New complexes of N-acetyl-D,L-penicillamine, 2-mercaptosuccinic acid, meso-dimercaptosuccinic acid, and Unithiol have been synthesized and characterized, and are found to have the formulations MeHgSCMe2CH(NHCOMe)CO2H, MeHgSCH(CO2H)CH2CO2H, MeHgSCH(CO2H)CH(CO2H)SHgMe, and Na[MeHgSCH2CH-(SHgMe)CH2SO3], respectively. Trends in octanol/water partition coefficients are consistent with reported studies of the effectiveness of antidotes for MeHg(II) poisoning and redistribution of MeHg(II) on administration of antidotes, particularly for British anti-Lewisite, Unithiol, and meso-dimercaptosuccinic acid.     

Isothiocyanates. A new class of uncouplers

This paper describes the uncoupling effect of three isothiocyanates: p-bromophenylisothiocyanate, 4,4′-diisothiocyanatebiphenyl and β-naphtylmethylisothiocyanate on the respiration of Ehrlich-Lettré cells and isolated mitochondria. The isothiocyanates are similar to other uncouplers (such as 2,4-dinitrophenol and carbonyl cyanide p-trifluoromethoxyphenylhydrazone) in that they: 1. stimulate respiration of state 4 mitochondria; 2. stimulate mitochondrial ATPase activity; 3. release the inhibition of mitochondrial respiration by oligomycin and 4. inhibit both mitochondrial respiration and mitochondrial ATPase activity at higher molar concentrations. The uncoupling activity of these isothiocyanates correlates well with their biological activity. Maximal activation of a latent mitochondrial ATPase activity of rat liver mitochondria in the presence of p-bromophenylisothiocyanate was found at a concentration of 15 μM. The investigated isothiocyanates differ significantly in their solubility in organic solvents and their chemical reactivity. We assume that the greater the partition coefficient in a series of isothiocyanates grouped according to the increasing value of log P (partition coefficient for the system octanol/water, 25 °C), the greater will be their uncoupling activity, but only up to a certain degree. Any further increase of log P will be marked by a decrease of this activity.