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In previous studies, we showed that a high-dose intake of green tea polyphenol (GP) induced a hepatospecific decrease in the expression and activity of the drug-metabolizing enzyme cytochrome P450 3A (CYP3A). In this study, we examined whether this decrease in CYP3A expression is induced by epigallocatechin gallate (EGCG), which is the main component of GP. After a diet containing 1.5% EGCG was given to mice, the hepatic CYP3A expression was measured. The level of intestinal bacteria of Clostridium spp., the concentration of lithocholic acid (LCA) in the feces, and the level of the translocation of pregnane X receptor (PXR) to the nucleus in the liver were examined. A decrease in the CYP3A expression level was observed beginning on the second day of the treatment with EGCG. The level of translocation of PXR to the nucleus was significantly lower in the EGCG group. The fecal level of LCA was clearly decreased by the EGCG treatment. The level of intestinal bacteria of Clostridium spp. was also decreased by the EGCG treatment. It is clear that the hepatospecific decrease in the CYP3A expression level observed after a high-dose intake of GP was caused by EGCG. Because EGCG, which is not absorbed from the intestine, causes a decrease in the level of LCA-producing bacteria in the colon, the level of LCA in the liver decreases, resulting in a decrease in the nuclear translocation of PXR, which in turn leads to the observed decrease in the expression level of CYP3A.

Background and Aim The expression levels of cytochrome P450 (CYP) in the liver were analyzed over time in dextran sulfate sodium (DSS)-induced ulcerative colitis mouse model, from the initial active stage to the remission stage, to investigate the relationship between the changes in pathological conditions and CYP expression levels. Methods DSS solution was given to mice for 10 days, after which water without DSS was provided for 40 days. Pathological conditions and CYP expression levels were examined over time. The mechanism for variation in CYP expression was also analyzed. Results The mRNA expression levels of CYP (CYP3A11, CYP1A2, CYP2C29, CYP2D9, and CYP2E1) decreased as pathological conditions worsened and reached their lowest levels on day 10 of DSS treatment. Pathological conditions improved following the discontinuation of DSS, and CYP expression levels normalized by day 50. Blood lipopolysaccharide levels, the hepatic expression of inflammatory cytokines, and the nuclear translocation of pregnane X receptor and constitutive androstane receptor in the liver exhibited patterns similar to the observed variations in CYP expression levels. Conclusion The capacity for metabolizing drugs that are substrates of CYP decreases during the active stage of ulcerative colitis but subsequently improves during the remission stage. This decrease in CYP expression was likely caused by the observed reduction in the levels of nuclearly localized pregnane X receptor and constitutive androstane receptor, and the increase in the production of inflammatory cytokines triggered by lipopolysaccharides.

Objectives: To determine cyclophosphamide exposure to preparers during tablet crushing and subsequent handling by analyzing indoor air collected using a high-performance volatile organic compounds-solvent desorption (VOC-SD) passive air sampler. Methods: The passive sampler was taped to the mask over the mouth of the preparer and indoor air was collected during crushing and preparation of cyclophosphamide tablets (Endoxan®). After collection, the carbon molecular sieve adsorbent of the passive sampler was placed in a centrifuge tube, and 1 mL of carbon disulfide was used to elute cyclophosphamide from the adsorbent. Liquid–liquid extraction with 1 mL of water was performed, and the aqueous phase was used as the test solution. Cyclophosphamide concentration was determined by liquid chromatography with ultraviolet and tandem mass spectrometry detection. Results: Cyclophosphamide concentration was detected in the range of 7.6–157.7 ng/sampler. Our results showed that low-level exposure occurred near the mouth of the preparer, which could present risks for long-term exposure, especially if combined with multiple toxic drug exposures. Conclusion: The anticancer drug monitoring methodology described here is a simple exposure assessment that can be used to ensure the safety of hospital pharmacy tablet preparers. Furthermore, since the anticancer drug exposure risk is very high for preparers, preparation should be in hood or with face mask.

Recently, it was reported that the anticoagulant effect of warfarin was reduced when patients receiving warfarin also took menthol. The purpose of this study is to reveal the mechanism of this reduced anticoagulant effect of warfarin from the pharmacokinetic point of view. Warfarin was orally administered to mice 24h after the administration of menthol for 2 days, and the plasma warfarin concentration was measured. In the menthol administration group, the area under the blood concentration time curve of warfarin was decreased by approximately 25%, while total clearance was increased to 1.3-fold compared to the control group. The hepatic cytochrome P450 (CYP) 2C protein expression level in the menthol administration group was significantly increased compared to that in the control group. An increase in the nuclear translocation of constitutive androstane receptor (CAR) was also observed. The addition of menthol to human hepatic cells, HepaRG cells, caused an increase in the mRNA expression level of CYP2C9. The results of this study revealed that menthol causes an increase in CYP2C expression levels in the liver, which leads to an enhancement of warfarin metabolism, resulting in a decreased anticoagulant effect of warfarin. It was also suggested that menthol acted directly on the liver and increased the expression level of CYP2C by enhancing the nuclear translocation of CAR.

The risk assessment of di(2-ethylhexyl)phthalate (DEHP) migration from polyvinyl chloride (PVC) medical devices is an important issue for patients. The aim of this study was to determine DEHP degradation and migration from PVC sheets. To this end, the method for the simultaneous determination of DEHP and its breakdown products (mono(2-ethylhexyl)phthalate (MEHP) and phthalic acid (PA)) was improved. Their migration levels from 0 to 50 kGy gamma-ray irradiated PVC sheets were determined. DEHP migration level decreased in proportion to the dose of gamma-ray irradiation, while MEHP and PA migration levels increased. The hardness and the elastic modulus of PVC sheets were examined, but no clear relationship between DEHP migration and these parameters was observed.

Tris(2-ethylhexyl)trimellitate (TOTM) is used as an alternative plasticizer of polyvinyl chloride (PVC) medical devices. A method for the determination of TOTM released from PVC medical devices into intravenous preparations was developed, which uses liquid chromatography-tandem mass spectrometry (LC–MS/MS). A PVC tube was filled with an intravenous preparation and extraction was carried out by shaking for 1 h at room temperature. LC was performed with an Inertsil ® -C8 (50 mm × 2.1 mm, 5 μm) column. The isocratic mobile phase was acetonitrile:purified water (90:10, v/v) at a flow rate of 0.2 ml/min. MS detection was accomplished with an MS/MS detector equipped with a turbo ionspray ionization source in the positive ion mode. The limit of detection and the limit of quantification for the standard solution of TOTM was 0.5 ng/ml (S/N = 3) and 1.0 ng/ml (S/N ≥ 10), respectively. When Prograf ® (tacrolimus) was used, the average recovery of TOTM was 101.1% (R.S.D. = 4.72%; n = 3). When our method was applied to the determination of TOTM released from unsterilized and gamma-ray-sterilized PVC tubes, we found that a higher concentration of TOTM was released from the unsterilized PVC tube than from the gamma-ray-sterilized one.