No abstract

S-methyl-l-methionine (SMM), also known as vitamin U, is commercially available as skin care cosmetic products for its wound healing and photoprotective effects. However, the low skin permeation expected of SMM due to its hydrophilic nature with a log P value of −3.3, has not been thoroughly addressed. The purpose of this study thus was to evaluate the effect of skin permeation enhancers on the skin permeation/deposition of SMM. Among the enhancers tested for the in vitro skin permeation and deposition of SMM, oleic acid showed the most significant enhancing effect. Moreover, the combination of oleic acid and ethanol further enhanced in vitro permeation and deposition of SMM through hairless mouse skin. Furthermore, the combination of oleic acid and ethanol significantly increased the in vivo deposition of SMM in the epidermis/dermis for 12 hr, which was high enough to exert a therapeutic effect. Therefore, based on the in vitro and in vivo studies, the combination of oleic acid and ethanol was shown to be effective in improving the topical skin delivery of SMM, which may be applied in the cosmetic production process for SMM.

A simple and sensitive analytical method for the quantitative determination of buspirone in rat plasma by HPLC with fluorescence detection was developed and validated using naproxen as an internal standard. A relatively small-volume (150 µL) aliquot of rat plasma sample was prepared by a simple deproteinization procedure using acetonitrile as a precipitating organic solvent. Chromatographic separation was performed using Kinetex ® C8 column with an isocratic mobile phase consisting of acetonitrile and 10-mM potassium phosphate buffer (pH 6.0) at a flow rate of 1.0 mL/min. The eluent was monitored by fluorescence detector at a wavelength pair of 237/380 nm (excitation/emission). The linearity was established at 20.0-5000 ng/ mL, and the limit of detection was 6.51 ng/mL. The precision (≤14.6%), accuracy (89.2-108%), and stability (89.1-101%) were within acceptable ranges. The newly developed method was successfully applied to intravenous and oral pharmacokinetic studies of buspirone in rats.Key words buspirone; HPLC; fluorescence detection; rat plasma; pharmacokinetics [4,5] decane-7,9-dione), an azapirone, is an antianxiety agent that has dopaminergic, noradrenergic, and serotonin-modulating activity.1) It is chemically unrelated to benzodiazepines or barbiturates, and it exerts a pharmacologically unique anxiolytic effect without sedative, muscle relaxant, and anticonvulsant properties.2,3) Oral buspirone formulation (e.g., Buspar ® ) is currently used in the treatment of anxiety disorders and the short-term relief of the symptoms of anxiety. 4) Orally administered buspirone is rapidly absorbed but it undergoes first-pass metabolism, resulting in a low bioavailability of less than 5%. 5,6) Buspirone is metabolized primarily by CYP450 3A4-mediated oxidation. 7,8) However, little information is available regarding important pharmacokinetic issues that include the exact reason for the low bioavailability, kinetics of organ clearance, and mechanisms of elimination of buspirone in animals or humans.9) Therefore, development of analytical tools for quantification of buspirone in various biological fluids will contribute to the progress of mechanistic pharmacokinetic and pharmacological studies of buspirone in a pre-clinical or clinical setting.A few analytical methods have been reported for the determination of buspirone in human plasma by HPLC with ultraviolet spectrophotometry (UV) method 2) and HPLC with tandem mass spectrometry (HPLC-MS/MS) method, 8,10) and in rabbit serum by HPLC-UV method.5) However, these methods have several limitations such as a relatively large sample volume (i.e., 500 µL) and costly and/or laborious sample preparation procedures that include a liquid-liquid or solid phase extraction. Moreover, mass spectrometry requires relatively expensive equipment and highly skilled technical expertise, which may not always be feasible for most laboratories in resource-limited settings.11) Previously, we reported the plasma concentration versus time profiles of buspirone in rats using a HPLC-UV method ...

Anacetrapib is a potent and selective CETP inhibitor and is undergoing phase III clinical trials for the treatment of dyslipidemia. A simple and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the quantification of anacetrapib in rat plasma was developed and validated using an easily purchasable compound, chlorpropamide, as an internal standard (IS). A minimal volume of rat plasma sample (20 μL) was prepared by a single-step deproteinization procedure with 80 μL of acetonitrile. Chromatographic separation was performed using Kinetex C column with a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid at a flow rate of 0.3 mL/min. Mass spectrometric detection was performed using selected reaction monitoring modes at the mass/charge transitions m/z 638 → 283 for anacetrapib and m/z 277 → 175 for IS. The assay was validated to demonstrate the selectivity, linearity, precision, accuracy, recovery, matrix effect and stability. The lower limit of quantification was 5 ng/mL. This LC-MS/MS assay was successfully applied in the rat plasma protein binding and pharmacokinetic studies of anacetrapib. The fraction of unbound anacetrapib was determined to be low (ranging from 5.66 to 12.3%), and the absolute oral bioavailability of anacetrapib was 32.7%.

The epidermal barrier function requires optimal keratinocyte differentiation and epidermal lipid synthesis. Liver X receptor (LXR) α and β, are important transcriptional regulators of the epidermal gene expression. Here, we show that raffinose, a ubiquitously present trisaccharide in plants, activated the transcriptional activity of LXRα/β, which led to the induction of genes required for keratinocyte differentiation such as involucrin and filaggrin, and genes involved in lipid metabolism and transport including SCD1 and ABCA1 in both HaCaT and normal human epidermal keratinocytes. Raffinose induced the expression of JunD and Fra1, and their DNA binding in the AP1 motif in the promoters of involucrin and loricrin. Interestingly, LXR bound the AP1 motif upon raffinose treatment, and conversely, JunD and Fra1 bound the LXR response element in promoters of LXR target genes, which indicates the presence of a postive cross-talk between LXR and AP1 in the regualtion of these genes. Finally, the effect of raffinose in epidermal barrier function was confirmed by applying raffinose in an ointment formulation to the skin of hairless mice. These findings suggest that raffinose could be examined as an ingredient in functional cosmetics and therapeutic agents for the treatment of cutaneous disorders associated with abnormal epidermal barrier function.