To elucidate the molecular mechanism(s) by which methyl salicylate enhances the skin delivery of herbal ingredients with diverse lipophilicity.

The toxicity of methyl salicylate on skin cell lines was evaluated using the MTT assay. The Franz diffusion cell method was used to measure the permeability enhancing activities of methyl salicylate for five herbal ingredients with a range of lipophilicities. The interaction between methyl salicylate and the stratum corneum (SC) was observed by using an infrared spectroscopy technique. Moreover, the solubilities and SC-vehicle partition coefficient were determined to monitor the impact of methyl salicylate on the drug thermodynamic activities and partition into the SC layer, respectively.

Compared with azone (1-dodecylazacycloheptan-2-one), methyl salicylate showed lower toxicity to skin cells in terms of the IC₅₀ values. The in vitro skin permeation studies showed that methyl salicylate could greatly improve the cumulative amounts or steady state flux of the selected model drugs with the exception of osthole, which indicated that methyl salicylate was prone to promote the skin delivery of hydrophilic drugs. The Fourier transform infrared spectroscopy studies revealed that methyl salicylate mainly interacted with SC lipids, leading to the disruption of the orderly arrangement of the SC. In addition, methyl salicylate had no obvious effect on the drug thermodynamic activity and partition into the SC.

Methyl salicylate could effectively promote the skin delivery of relatively hydrophilic ingredients in externally used traditional Chinese medicines (TCM) without obvious cytotoxicity.

Pretreatment of biological samples is the most critical step in pharmacokinetic studies, especially pre-treatment of plasma samples. The pretreatment of biological samples in pharmacokinetic study of Traditional Chinese Medicines (TCM) is difficult due to the complexity of the ingredients. An organic solvent system ethyl acetate: acetone (10: 1) solution used for liquid-liquid extraction has been developed in this study and compared with the commonly used protein precipitation method.

Rats, Beagle dogs and humans plasma samples were adopted in this study in order to demonstrate the universality of the pretreatment method. Feasibility of this pretreatment method was also verified through its application to the pharmacokinetics of rhubarb in rats.

According to the results of extraction recovery matrix effect, it was indicated that the liquid-liquid extraction methods with new organic solvent might be suitable for variety of structures of compounds and various types of plasma samples. The pharmacokinetic study result showed that the developed pretreatment method could successfully be used for simultaneous determination of three active compounds modin, emodin-8-O-β-D-glucopyranoside (EDG) and rhein in rat plasma with high sensitivity, accuracy, and recovery by liquid chromatography tandem mass spectrometry (LC-MS/MS).

The pretreatment method of liquid-liquid extraction methods with new organic solvent could be successfully applied for multi-component pharmacokinetics of TCM.

To investigate the percutaneous penetration enhancement effect of essential oil from Zanthoxylum bungeanum Maxim. (Z. bungeanum oil) on active components in externally-applied traditional Chinese medicines.

Five model drugs, geniposide, puerarin, ferulic acid, tetramethylpyrazine, and osthole, were chosen based on their lipophilicity and tested using in vitro transdermal permeation studies consisting of Franz diffusion cells and full thickness rat abdominal skin. Scanning electron microscopy was employed to observe the morphological changes of rat skin tissue after treatment with Z. bungeanum oil. The molecular interactions between the oil and the polar head groups in stratum corneum (SC) lipids were monitored using molecular dynamic simulation, and the SC/vehicle partition coefficients and saturation solubilities of the selected model drugs treated with and without the oil were also determined to ascertain its mechanisms of action.

As oil concentration increased, the log ER_flow trended toward a negative linear relationship with the lipophilicity of drugs. After treatment with Z. bungeanum oil, a mild lifting up and wrinkle on the SC surface were observed, and appeared to become more pronounced as oil concentration increased. There was no significant difference between the control and the Z. bungeanum oil at different concentrations in terms of saturation solubility of GP, while saturation solubilities of the 4 other drugs gradually increased as oil concentration increased. The oxygen-containing constituents in Z. bungeanum oil, such as terpinen-4-ol and 1,8-cineole, which accounted for 57.95% of total oil, could form stable hydrogen bonds with the polar head group of ceramide 3.

Z. bungeanum oil facilitated transdermal permeation of drugs with different lipophilicity, including the extremely hydrophilic and lipophilic drugs, whereas it exhibited greater enhancement activity for strongly hydrophilic drugs. The mechanisms of transdermal permeation enhancement by the oil could be explained with SC/vehicle partition coefficient, saturation solubility, and the interactions with SC lipids.

To establish a basis for Angelica Sinensis Radix (ASR) as a dietary supplement for colorectal cancer chemoprevention, the effect of co-existent components in supercritical fluid extract (SFE) of ASR on the pharmacokinetics of Z-ligustilide after oral administration was investigated in vitro and in vivo.

Incubation in gastrointestinal contents and incubation in rat liver tissue homogenates post-mitochondrial supernatant (PMS) experiments were used to study changes in the levels of Z-ligustilide in vitro.

Within 4 hours, the level of Z-ligustilide in SFE declined at a slower rate than in its pure form. Clearance of Z-ligustilide after administration in its pure form was significantly slower than that of SFE of ASR (CL, 0.96 ± 0.16 mL·min/kg versus 1.24 ± 0.21 mL·min/kg P < 0.05; AUC, 243.37 ± 16.84 versus 176.69 ± 12.59 mg·min/L).

These phenomena may be attributed to the interactions between the co-existent components in SFE of ASR and Z-ligustilide enhancing the stability of Z-ligustilide. These results suggest that the bioavailability of Z-ligustilide in SFE of ASR is improved. However, stabilization of plasma concentration was not sustained, so that the efficacy of active components could not be maintained. Thus, further processing of SFE of ASR is required.

To investigate the percutaneous penetration effect of essential oil of mint from Mentha haplocalyx Briq. on the complex active components in Chinese herbal external preparations, and assess its toxicity on the skin cells.

The cytotoxicity of mint oil on HaCaT keratinocytes and CCC-ESF-1 fibroblasts was measured using an MTT assay. Five model drugs with a wide range of lipophilicity, namely osthole, tetramethylpyrazine, ferulic acid, puerarin, and geniposide, were tested using in vitro permeation studies to investigate the percutaneous penetration enhancement effect of mint oil. Secondary structure alterations of skin stratum corneum (SC) were measured using Fourier transform infrared spectroscopy (FTIR). Saturation solubilities and SC/vehicle partition coefficients of the five model drugs with and without mint oil were also determined to understand the potential mechanisms of the essential oil.

Half maximal inhibitory concentration (IC₅₀) values of mint oil were significantly higher in HaCaT and CCC-ESF-1 cell lines than values in the well-established and standard penetration enhancer Azone.

Mint oil at proper concentration could effectively facilitate percutaneous penetration of both lipophilic and hydrophilic drugs, and exhibit higher efficiency for moderate hydrophilic drugs. Mechanisms of penetration enhancement by mint oil could be explained with saturation solubility, SC/vehicle partition coefficient and the secondary structure change of SC.