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Objectives The current study aims to determine the effect of physicochemical descriptor selection on models of polydimethylsiloxane permeation. Methods A total of 2942 descriptors were calculated for a data set of 77 chemicals. Data were processed to remove redundancy, single values, imbalanced and highly correlated data, yielding 1363 relevant descriptors. For four independent test sets, feature selection methods were applied and modelled via a variety of Machine Learning methods. Key findings Two sets of molecular descriptors which can provide improved predictions, compared to existing models, have been identified. Best permeation predictions were found with Gaussian Process methods. The molecular descriptors describe lipophilicity, partial charge and hydrogen bonding as key determinants of PDMS permeation. Conclusions This study highlights important considerations in the development of relevant models and in the construction and use of the data sets used in such studies, particularly that highly correlated descriptors should be removed from data sets. Predictive models are improved by the methodology adopted in this study, notably the systematic evaluation of descriptors, rather than simply using any and all available descriptors, often based empirically on in vitro experiments. Such findings also have clear relevance to a number of other fields.

There is increasing concern that infants and children may be at increased risk of neurological effects of pyrethroids, the most widely used class of insecticide. The objectives of this investigation were to (1) characterize the dose-dependent toxicokinetics (TK) of deltamethrin (DLM) for exposures ranging from environmentally relevant to acutely toxic; (2) determine the influence of an aqueous versus oil vehicle on oral absorption and bioavailability; and (3) determine whether DLM exhibits low-dose, age-equivalent internal dosimetry. Serial arterial plasma samples were obtained for 72 h from adult, male Sprague Dawley rats given 0.05-5.0 mg DLM/kg as an oral bolus in corn oil (CO). DLM exhibited linear, absorption rate-limited TK. Increases in maximum plasma concentration (Cmax) and AUC∘∞ were directly proportional to the dose. Oral bioavailability was quite limited. The vehicle and its volume had modest effect on the rate and extent of systemic absorption in adult rats. Postnatal day (PND) 15, 21, and 90 (adult) rats received 0.10, 0.25, or 0.50 mg DLM/kg orally in CO and were sacrificed periodically for plasma, brain, and liver collection. Age-dependent differences between PND 15 and 90 plasma Cmax and AUC∘24 values progressively diminished as the dose decreased, but there was a lack of low dose age equivalence in these brain and liver dosimeters. Other maturational factors may account for the lack of the low-dose age equivalence in brain and liver. This investigation provides support for the premise that the relatively low metabolic capacity of immature subjects may be adequate to effectively eliminate trace amounts of DLM and other pyrethroids from the plasma.

The polyunsaturated fatty acids (PUFA) arachidonic acid (AA, n-6) and eicosapentaenoic acid (EPA, n-3) are precursors of eicosanoids and other lipid mediators which have critical roles in inflammation. The mediators formed from the different PUFA have different potencies. We hypothesised that metabolic changes associated with colonic mucosal inflammation would modify the bioavailability of the eicosanoid precursors AA and EPA.Colonic mucosa biopsies were obtained from patients with ulcerative colitis and from matched controls. Inflammation was graded endoscopically and histologically. Esterified and non-esterified fatty acids were determined within the biopsies using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry, respectively.Biopsy samples were collected from 69 UC patients (54 providing both inflamed and non-inflamed mucosa) and 69 controls. Inflamed mucosa had higher AA (p0.001) and lower EPA (p0.010) contents and a higher AA:EPA ratio (p0.001). Inflamed mucosa also had higher docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) and lower linoleic acid (LA) and α-linolenic acid (α-LNA) contents (all p0.001), compared to non-inflamed and controls. There were significant correlations between severity of inflammation and contents of AA, DPA and DHA (positive correlations) and of LA, α-LNA and EPA (negative correlations).Higher AA, AA:EPA ratio, DPA and DHA and lower LA, α-LNA and EPA are seen in inflamed mucosa in UC and correlate with severity of inflammation. This suggests an alteration in fatty acid metabolism in the inflamed gut mucosa, which may offer novel targets for intervention and should be considered if nutritional strategies are used.

An improved bioanalytical method to determine pyrethroids from small-volume (300 μL) rat liver and muscle homogenates was developed, validated, and applied to small-animal studies. The method used dispersive SPE (d-SPE) to clean the samples, and GC negative chemical ion MS (GC-NCI-MS) to analyze the samples. High-quality trace analysis of pyrethroids in biological samples was necessary to assess the health risk of environmentally encountered levels. Currently used highly sensitive methods to measure pyrethroids have focused on large-volume samples related to environmental exposure (water, soil, food products) or urine; however, there are no validated methods for quantifying this class of compounds in small-volume rat liver and muscle tissue homogenates. Individual rat tissue homogenate samples (300 μL) were prepared by protein precipitation using hexane-saturated acetonitrile. The samples were mixed on a vortex mixer and decanted into a d-SPE tube containing octadecylsilyl (C18) and primary secondary amine (PSA) sorbents and magnesium sulfate. The samples were centrifuged before evaporation to dryness. Pyrethroids were extracted and reconstituted from the residue using toluene in advance of injection into an Agilent Model 6890N gas chromatograph equipped with a Model 5973 quadrupole mass analyzer. Samples were ionized via electron capture in the negative ion mode using methane as a chemical ionization gas. Six qualifying ions were monitored using selected-ion monitoring for quantitation and verification of the analyte. Cis-permethrin was used as the internal standard. Method linearity was from 1 to 500 ng/mL for muscle and liver homogenates. The inter- and intraday precision and accuracy of the method were better than 20% at the lower LOQ and better than 15% over the remainder of the linear range. The method was used to elucidate tissue time-courses of deltamethrin (DLM) disposition following oral dosing of rats with 1 to 5 mg/kg in corn oil. DLM was monitored in rat tissue samples ≤24 h following dosing. Sample cleanup with d-SPE provided more selective chromatography than previous analytical methods.

Objectives To determine the metabolism of captopril n-carboxyl derivatives and how this may impact on their use as transdermal prodrugs. The pharmacological activity of the ester derivatives was also characterised in order to compare the angiotensin converting enzyme inhibitory potency of the derivatives compared with the parent drug, captopril. Methods The metabolism rates of the ester derivatives were determined in vitro (using porcine liver esterase and porcine ear skin) and in silico (using molecular modelling to investigate the potential to predict metabolism). Key findings Relatively slow pseudo first-order metabolism of the prodrugs was observed, with the ethyl ester displaying the highest rate of metabolism. A strong relationship was established between in-vitro methods, while in-silico methods support the use of in-vitro methods and highlight the potential of in-silico techniques to predict metabolism. All the prodrugs behaved as angiotensin converting enzyme inhibitors, with the methyl ester displaying optimum inhibition. Conclusions In-vitro porcine liver esterase metabolism rates inform in-vitro skin rates well, and in-silico interaction energies relate well to both. Thus, in-silico methods may be developed that include interaction energies to predict metabolism rates.

Most drugs are designed primarily for oral administration, but the activity and stability profiles desirable for this route often make them unsuitable for transdermal delivery. We were therefore interested in designing analogues of captopril, a model drug with poor percutaneous penetration, for which the sustained steady-state blood plasma level associated with transdermal delivery (and which is unattainable orally) would be particularly beneficial. Quantitative structure—permeability relationships (QSPRs) predicted that ester and thiol prodrug derivatives of captopril would have lower maximal transdermal flux (Jm) than the parent drug, since the increases in permeability coefficient (kp) of prodrugs would be outweighed by the reductions in aqueous solubility. Therefore, the aim of this study was to synthesize a series of prodrugs of captopril and to determine if a QSPR model could be used to design therapeutically viable prodrugs. Molecules with the highest predicted kp values were synthesized and characterized, and Jm measured in Franz diffusion cells from saturated aqueous donor across porcine skin (fresh and frozen). In-vitro metabolism was also measured. Captopril and the prodrugs crossed the skin relatively freely, with Jm being highest for ethyl to butyl esters. Substantial first-order metabolism of the prodrugs was observed, suggesting that their enhanced percutaneous absorption was complemented by their metabolic performance. The results suggested that QSPR models provided excellent enhancements in drug delivery. This was not seen at higher lipophilicities, suggesting that issues of solubility need to be considered in conjunction with any such use of a QSPR model.

Introduction The polyunsaturated fatty acids (PUFA) arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) are generated from dietary essential fatty acids linoleic acid (LA) and α-linolenic acid (αLNA) and direct dietary intake. AA and EPA are substrates for eicosanoid inflammatory mediators that may have critical roles in immunomodulation in Ulcerative Colitis (UC). Dietary supplementation studies alter the availability of specific PUFA (eg, EPA), but clinical studies have been disappointing leading to the hypothesis that the PUFA biosynthetic pathway in inflamed tissue may be altered. This study evaluated PUFA bioavailability in inflamed and uninflamed mucosa from UC patients and compared to matched controls. Methods Ethical approval was obtained. Patients were prospectively recruited from outpatients9 clinics. Mucosal biopsies at flexible sigmoidoscopy (FS) were taken from active UC patients within inflamed (active) and endoscopically normal proximal mucosa (internal control). Age-sex matched patients undergoing FS for IBS or similar presentations were compared (external controls). Mucosal samples were saponified, deuterated internal standards added, lipids hydrolysed and fatty acids derivatised prior to liquid-liquid extraction into heptane. PUFA were quantified by gas chromatography mass spectrometry. Data was expressed as percentage mass abundance and compared using Wilcoxon signed rank pair analysis for non-parametric data. Results 69 active UC patients (54 paired normal/inflamed mucosa) and 69 controls were compared. No biologically significant differences were noted between endoscopically normal mucosa from UC patients and external controls other than DPA (p Conclusion PUFA bioavailability within normal mucosa in UC patients is not significantly different from matched controls; however, inflamed mucosa demonstrates significant differences in the bioavailability of PUFA with a reduction in LA and αLNA and a divergent change in AA and EPA leading to a significant increase in the AA/EPA ratio. These findings suggest alteration of the fatty acid biosynthetic pathway in inflamed tissue and may suggest that alternative therapeutic strategies are required to modify the eicosanoid profile in UC.

Introduction Ulcerative colitis (UC) is a colonic inflammatory disorder of unconfirmed aetiology. Eicosanoids, inflammatory mediators involved in UC pathogenesis, are enzymatically converted from dietary polyunsaturated fatty acids (PUFA), arachidonic acid (AA) and eicosapentaenoic acid (EPA), themselves competitive substrates also generated via a fatty acid (FA) biosynthetic cascade. Dietary studies using fish oil-derived EPA have been disappointing in UC; we hypothesised that the PUFA biosynthetic pathway in inflamed tissue is altered. This study evaluated PUFA profile in inflamed and non-inflamed mucosa from UC patients and compared to matched controls. Methods Ethical approval was obtained. Patients were prospectively recruited from outpatients9 clinics. Mucosal biopsies at flexible sigmoidoscopy (FS) were taken from UC patients within inflamed and normal proximal mucosa. Age-sex matched control patients undergoing FS for functional symptoms were compared. Inflammation was scored endoscopically and histologically. Membrane bound FA (MBFA): Biopsies were spiked with deuterated internal standard, followed by liquid-liquid extraction and quantitative gas chromatography mass spectrometry (MS). Free Fatty Acid (FFA): Biopsies were homogenised, followed by solid phase extraction and liquid chromatography orbitrap MS. Data were expressed as percentage abundance. Dietary fatty acid analysis was undertaken. Wilcoxon signed rank pair and Spearman9s correlation analysis were employed. Results 69 active UC patients (54 paired normal/inflamed mucosa) and 69 controls were compared. No biologically significant differences were noted between endoscopically normal mucosa from UC patients and controls other than DPA (p Conclusion Mucosal PUFA bioavailability is altered in active UC, with significant elevation of AA and reduction of LA, αLNA and EPA. This suggests modification of the FA biosynthetic pathway with elevated delivery of AA as a precursor of pro-inflammatory eicosanoids in active UC. These findings may explain the lack of efficacy of supplemental fish oil and suggests new alternative therapeutic targets. Competing interests None declared.