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U W Kesselring

Publications and source records attributed to U W Kesselring.

At least 19 recordsLinked to original sources
PubMed2001

Extractionless method for the simultaneous high-performance liquid chromatographic determination of urinary caffeine metabolites for N-acetyltransferase 2, cytochrome P450 1A2 and xanthine oxidase activity assessment.

Urinary metabolic ratios of caffeine are used in humans to assess the enzymatic activities of cytochrome P450 isoenzyme 1A2 (CYP1A2), xanthine oxidase (XO) and for phenotyping individuals for the bimodal N-acetyltransferase 2 (NAT2), all of them involved in the activation or detoxification of various xenobiotic compounds. Most reported analytical procedures for the measurement of the urinary metabolites of caffeine include a liquid-liquid extraction of urine samples prior to their analysis by reversed-phase HPLC. At neutral to basic pH however, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), a metabolite of caffeine, spontaneously decomposes to 5-acetylamino-6-amino-3-methyluracil (AAMU). Since AAMU is not extracted in most organic solvents, the extent of AFMU decomposition cannot be precisely assessed. Although the decomposition reaction can be minimized by immediate acidification of the urine, accurate results can only be obtained when both AAMU and AFMU are monitored, or alternatively, if AAMU is measured after complete transformation of AFMU into AAMU in basic conditions. We report a liquid chromatographic method for the simultaneous quantitative analysis of the five urinary metabolites of caffeine used for the CYP1A2, XO and NAT2 phenotyping studies: AAMU, AFMU, 1-methylxanthine, 1-methyluric acid and 1,7-dimethyluric acid. These metabolites are satisfactory separated from all other known caffeine metabolites as well as endogenous urinary constituents. Sample treatment does not require any liquid-liquid extraction procedure. Urine samples are diluted and centrifuged before being injected (10 microl) onto a YMC-Pack Polyamine II (250x4.6 mm) column. A step-wise gradient elution program is applied using acetonitrile-0.75% (v/v) formic acid: (91:9) at 0 min-->(75:25) at 25 min-->(65:35) at 35 min-->(65:35) at 45 min, followed by a re-equilibration step to the initial solvent composition. The flow-rate is 1.0 ml/min and the separations are monitored by UV absorbance at 260 and 280 nm. The procedure described here represents a substantial improvement over previous methods: a single analysis and a minimal urine sample treatment enables the simultaneous quantitation of five caffeine metabolites, notably AFMU and AAMU, used for the determination of CYP450 1A2, XO and NAT2 enzyme activity. Importantly enough, phenotyping individuals for the bimodal NAT2 is made possible without the uncertainty associated with the deformylation of AFMU, which is likely to happen at all steps prior to the analysis, during sample storage and even in the bladder of the subjects.

Arylamine N-Acetyltransferase↗
PubMed2001

Validation of an HPLC method for the determination of urinary and plasma levels of N1-methylnicotinamide, an endogenous marker of renal cationic transport and plasma flow.

N1-Methylnicotinamide (NMN) is an endogenous cationic metabolite of nicotinamide (niacine, vitamine PP) whose renal clearance reflects both the capacity of the renal tubular transport system to secrete organic cations and renal plasma flow. NMN is present in human plasma and urine at the 1-117-ng ml(-1) and 0.5-25-microg ml(-1) concentration range, respectively, and its level depends notably on pathophysiological (age, renal or hepatic diseases) conditions. We report the optimization and validation of an HPLC method for the measurement of endogenous NMN in biological fluids after derivatization into a fluorescent compound. Plasma is first deproteinized with TCA 20% and the urine diluted 1:10 with HCI 10(-4) M prior to the derivatization procedure, which includes a condensation reaction of NMN with acetophenone in NaOH at 0 degrees C, followed by dehydration in formic acid and subsequent formation of the fluorescent 1,6-naphthyridine derivatives after heating samples in a boiling water bath. The synthetic homologous derivative N1-ethylnicotinamide (NEN) reacts similarly and is added as internal standard into the biological fluid. The reaction mixture is subjected to reverse phase high performance liquid chromatography on a Nucleosil 100-C18 column using a mobile phase (acetonitrile 22%, triethylamine 0.5%, 0.01 M sodium heptanesulfonate adjusted to pH 3.2), delivered isocratically at a flow rate of 1 ml min(-1), NMN and NEN are detected at 7.8 and 10 min by spectrofluorimetry with excitation and emission wavelengths set at 366 and 418 nm, respectively. The addition-calibration method is used with plasma and urine pools. Calibration curves (using the internal standard method) are linear (r2 > 0.997) at concentrations up to 109 ng ml(-1) and 15.7 microg ml(-1) in plasma and urine, respectively. Both intra- and inter-assay precision of plasma control samples at 10, 50 and 90 ng ml(-1) were lower than 3.3% and concentrations not deviating more than 2.7% from their nominal values. In urine intra- and inter-assay CVs of control samples at 1, 5 and 9 microg ml(-1) are lower than 8.3%, with concentrations not deviating more than -9.0 to +11.8% from their nominal values. This analytical method has therefore the required sensitivity and selectivity to measure NMN in plasma and urine, enabling the non-invasive determination of the tubular secretory capacity of the kidney and the renal plasma flow.

Biomarkers↗
PubMed1998

The hydrophobic effect. 1. A consequence of the mobile order in H-bonded liquids.

The hydrophobic effect has an entropic nature that cannot be explained by classical multicomponent treatments that do not explicitly take into account both the mobility and the nonergodicity of the H-bonds in amphiphilic liquids. The nonergodic thermodynamics of mobile order in H-bonded liquids based on time fractions rather than on concentrations provides a novel qualitative and quantitative explanation for the molecular origin of the hydrophobic effect. Chiefly, this effect corresponds to the loss of the mobile order entropy of associated molecules by dilution with foreign substances. Not being a unique property of water, the propensity of an amphiphilic solvent to induce a solvophobic effect increases primarily as its structuration factor increases, and secondarity as the solute/solvent molar volume ratio increases. On this basis, it can be expected that in the absence of strong solute-solvent specific interactions, the solubility of nonelectrolytes will generally decrease in the following order: butanol > propanol > ethanol > methanol > propylene glycol > ethylene glycol > formamide > water.

Chemical Phenomena↗
PubMed1998

The hydrophobic effect. 2. Relative importance of the hydrophobic effect on the solubility of hydrophobes and pharmaceuticals in H-bonded solvents.

The quantitative development of the nonergodic mobile order thermodynamics involving the new interpretation of the hydrophobic effect leads to a general solubility equation. This equation is applied to predict the aqueous and alcohol solubility of chemicals ranging from nonpolar or slightly polar with no H-bonding capacity to polyfunctional polar compounds including pharmaceuticals. The analysis of the relative importance of the contributions involved in the solubility model [i.e., the fluidization of the solute (for solids), the correction for the mixing entropy, the change of the nonspecific cohesion forces, and the formation of solvent-solvent (hydrophobic effect), solute-solute, and solute-solvent H-bonds] unambiguously demonstrates that the hydrophobic effect is essential for predicting the aqueous or alcohol solubility of any substance in general, and of nonpolar compounds in particular. The difference between the origin of the solubility of hydrocarbons in water and of water in hydrocarbons is furthermore presented. In both cases, the quasilinear solubility dependence on the molar volume of the hydrocarbon is of an entropic nature.

Chemical Phenomena↗
PubMed1998

The hydrophobic effect. 3. A key ingredient in predicting n-octanol-water partition coefficients.

The quantitative development of the mobile order theory in H-bonded liquids is extended to predict the n-octanol/water partition coefficient (P). The log P predictive equation strictly issued from a thermodynamic treatment reduces to a simple linear volume-log P relationship whose intercept and slope encode, respectively, the solvation and entropy effects. For noncomplexing substances, the partition coefficient values result from two volume-dependent entropic contributions reflecting (a) the difference in the exchange entropy between the solute and solvent molecules in the n-octanol and water phases, and (b) the propensity difference between the two H-bonded solvents to induce a hydrophobic effect toward the solute. Although both effects increase, although with opposite signs, compared with the growing molar volume of the partitioned compound, the hydrophobic contribution always predominates favoring the transfer of the solute into the organic phase and hence increasing its partition coefficient. When dealing with complexing chemicals, the hydrophobic effect-related term, though remaining the dominant factor in most cases, is more or less counterbalanced by the formation of H-bonds between the interacting sites of the solute and the n-octanol and water solvent molecules. The log P, corrected for the substantial content of water into n-octanol, is estimated for a number of compounds of environmental and pharmaceutical interest. The extent to which the entropic and enthalpic factors affect the overall partition coefficient value is analyzed.

Chemical Phenomena↗
PubMed1997

The hydrophobic propensity of water toward amphiprotic solutes: predicton and molecular origin of the aqueous solubility of aliphatic alcohols.

A quantitative expression of the hydrophobic effect for amphiphilic solutes in water is developed in the frame of the nonergodic thermodynamics of mobile order in hydrogen-bonded liquids. In the case of aliphatic alcohols, the new expression leads to reduction of the hydrophobic propensity of water with respect to that exerted towards substances with no hydrogen bonding capacity. The reduction originates from the possible insertion of the alcohol molecules in the weakest hydrogen bond chain of water; hence, strengthening the hydrogen bonding network of water. Combined with the previous solubility model derived from mobile order thermodynamics, the new expression allows correct predictions of the solubility of 86 liquid and solid branched- and straight-chain alcohols in water at 25 degrees C, and provides better understanding of their behavior in aqueous solution. The model is furthermore applied to the estimation of the aqueous solubility of 12 monohydroxysteroids.

Alcohols↗
PubMed1996

Determination of the polyfructosan sinistrin in biological fluids by HPLC with electrochemical detection.

A sensitive HPLC method with electrochemical detection was developed for the determination of the polyfructosan sinistrin in human plasma and urine. Proteins and interfering components such as glucose were removed from plasma and urine samples by solid phase extraction on C18 cartridges. Chromatographic separations were achieved at 85 degrees C on a 300 mm x 7.8 mm i.d. column, using ion moderated partition chromatography with distilled water at a flow rate of 0.6 ml min-1. After post-column addition of NaOH 0.3 M (0.6 ml min-1), the electrochemical detection of the eluate was performed with a sequence of three potentials (0.05 V, -0.8 V, 0.6 V) of specific pulse duration 300, 100 and 100 ms respectively. Xylose was used as internal standard for the quantitative determinations. The calibration curves were linear (r2 > 0.992) over the working range 5-300 micrograms ml-1. This method has been characterized, validated and applied successfully in a study comparing two modes of glomerular filtration rate determination in healthy volunteers (bolus vs. constant rate infusion of sinistrin).

Chromatography, High Pressure Liquid↗
PubMed1994

Hydrophobic effect at the origin of the low solubility of inert solid substances in hydrogen-bonded solvents.

The new solubility equation derived from the thermodynamics of mobile order in liquids is used to predict the solubility of four solid aliphatic and aromatic hydrocarbons, namely, tricosane, octacosane, biphenyl and pyrene, in nonassociated and hydrogen-bonded solvents. The analysis of the relative importance of the different terms contributing to the solubility shows that (1) the fluidization of the solute always represents a barrier to the solubility, (2) in non-hydrogen-bonded solvents, the solubility essentially results from the balance of the exchange entropy correction and the change in the nonspecific cohesion forces upon mixing, (3) in alcohols or in water, the solubility is mainly determined by the hydrophobic effect which corresponds to a solute rejecting effect of the solvent. This effect is responsible for the lower solubility values of the inert substances in associated solvents with respect to those in nonassociated solvents.

Chemical Phenomena↗
PubMed1994

Solubility predictions for solid nitriles and tertiary amides based on the mobile order theory.

The solubilities of hexadecanenitrile, octadecanenitrile, N,N-diphenyl capramide, and N,N-diphenyl lauramide are predicted in common organic nonelectrolyte solvents using the solubility equation derived from the mobile order theory. In the framework of this theory, the formation of hydrogen bonds is treated on the basis of stability constants. Two values characterizing the nitrile-alcohol and the tertiary amide-alcohol hydrogen bonds, 175 and 600 cm3 mol-1, respectively, are determined. Although the formation of solute-solvent specific molecular interactions brings about a net increase in the solubility, the solubilities of the nitriles and amides in alcohols remain lower than those measured in nonassociated solvents because of the large negative hydrophobic effect of the alcohol molecules.

Amides↗
PubMed1992

Enhancement of the solubilities of polycyclic aromatic hydrocarbons by weak hydrogen bonds with water.

The thermodynamics of mobile order is applied to predict the aqueous solubility of liquid and solid aliphatic and polycyclic aromatic hydrocarbons. The solubility values are mainly determined by the magnitude of the hydrophobic effect. However, contrary to the solubilities of the alkanes, the solubilities of polycyclic aromatic hydrocarbons in water predicted in absence of solute-solvent hydrogen (H) bonds are systematically too low. This shows the contribution of weak specific interactions between the OH groups and the pi electrons of the aromatic substances. According to the theory, these interactions are characterized by a stability constant KO which can be derived from solubility data. At 25 degrees C, this constant amounts to 80 cm3/mol, the order of magnitude of which can be explained by the competition of these intermolecular bonds with the rather weak self-association bonds in the secondary chains of water.

Hydrocarbons↗
PubMed1992

The mobile order theory versus UNIFAC and regular solution theory-derived models for predicting the solubility of solid substances.

The theory of mobile order of Huyskens is tested against the UNIFAC model, the regular solution model, and the extended Hildebrand or Hansen solubility approaches in predicting the solubility of naphthalene in both polar and nonpolar solvents at 40 degrees C. While all models correctly predict the solubility in nonpolar and moderately polar solvents, a substantial improvement is achieved by Huyskens' model, particularly in alcohols. This improvement originates from the correct description of the entropy effects as well as of the hydrophobic effects in the particular case of the alcohols. The model necessitates the knowledge of only one parameter not known a priori, i.e., the naphthalene modified nonspecific solubility parameter, the value of which is deduced from its solubility in hexane.

Models, Chemical↗
PubMed1991

Significance of partial and total cohesion parameters of pharmaceutical solids determined from dissolution calorimetric measurements.

The total and partial adhesion-derived cohesion parameters of three solid pharmaceutical substances (caffeine, theophylline, and phenylbutazone) were determined from dissolution calorimetric measurements, a new technique devised for this purpose. Calorimetry has the advantage of leading directly to enthalpies, from which the solute cohesion parameter(s) is(are) deduced. An equation was developed that relates partial molar enthalpies of mixing (obtained by subtracting enthalpies of fusion from enthalpies of dissolution) to the cohesion parameters of the solute and of the solvents. Solvents were selected on the basis of their known cohesion parameters by applying the experimental research methodology.

Caffeine↗
PubMed1991

A new predictive equation for the solubility of drugs based on the thermodynamics of mobile disorder.

The thermodynamics of mobile disorder rejects the static model of the quasi-lattice for liquids. Because cause of the perpetual change of neighbors, during the observation time of thermodynamics of the order of seconds, each molecule of a given kind in a solution has experienced the same environment and had at its disposal the same mobile volume. This domain is not localizable and not orientable. Each molecular group perpetually "visits" successively all parts of this domain. The highest entropy is obtained when the groups visit all the parts of the domain without preference. H-bonds are preferential contacts with given sites of the neighbors that cause deviations with respect to such "random" visiting, thereby decreasing the entropy. The quantitative development of these ideas leads to equations describing the effect of solvent-solvent, solute-solvent, and solute-solute hydrogen bonds on the chemical potential of the solute. A universal equation predicting the solubility of drugs in a given solvent is derived. The effect of H-bonds is governed not by "solubility parameters" but by stability constants from which the order of magnitude can be estimated. From the sole knowledge of the solubility of methylparaben in pentane, the method predicts correctly the order of magnitude of its solubility in 26 other solvents, including alcohols and water.

Chemical Phenomena↗
PubMed1988

Determination of the total and partial cohesion parameters of lipophilic liquids by gas-liquid chromatography and from molecular properties.

The total and partial cohesion parameters of seven lipophilic liquids (one alkane, two alcohols, one acid, and three esters) have been determined. The proposed procedure involves knowledge of the structure, and determination of dipole moment, refractive index, and dielectric constant of the substances. The total cohesion parameters are experimentally determined for four liquids by gas-liquid chromatography, and also calculated for these and three additional liquids according to Fedors by summation of group increments. The dispersion cohesion parameter is calculated from the refractive index, and the polar cohesion parameter by Taft's polarity function, and Carr's relationship. The hydrogen bonding cohesion parameter is then obtained by difference. The results are self-consistent and coherent. In particular, it may be seen that the difference between the various lipophilic liquids, from the point of view of intermolecular interactions, is essentially due to the variation in strength of hydrogen bonds and dipole-dipole interactions, whereas the interactions stemming from the dispersion forces are similar.

Chromatography, Gas↗
PubMed1987

Determination of partial and total cohesion parameters of caffeine, theophylline, and methyl p-hydroxybenzoate by gas-solid chromatography.

For the first time, the total and partial solubility parameters, delta t, delta d, and delta s, of caffeine, theophylline, and methyl p-hydroxybenzoate were obtained by gas-solid chromatography (from the adsorption internal energy), by using the Keller, Karger, and Snyder equation. In comparison with the solubilization techniques, this method has the advantage of giving single solubility parameter values. The experimental work has been reduced to a minimum by the optimization of the matrix of experiments, according to the D-criterion, without any diminution in the quality of the results.

Caffeine↗
PubMed1986

Determination of partial solubility parameters of lactose by gas-solid chromatography.

On the basis of the Snyder/Karger-Hansen interaction model, where delta EA = Vi(delta di delta dj + delta pi delta pi + delta hi delta nj), the partial solubility parameters of a solid used as the stationary phase may be determined through gas-solid chromatography by null-injection of solutes with known solubility parameters. Using n-decane, acetonitrile, and 1-propanol as molecular probes, the values found for unhydrated lactose were 9.6, 12.8, 11.3, and 19.5 (cal1/2/cm3/2) for delta d, delta p, delta h, and delta t, respectively; relative standard errors were better than 3%. The choice and the minimum number of the best molecular probes were determined by optimization of the experimental matrix according to the D-criterion, which permits considerable reduction of experimental time yet enhances total precision.

Chemical Phenomena↗