Health risk assessment for human mercury exposure from Cinnabaris-containing Baizi Yangxin Pills in healthy volunteers Po administration.

BACKGROUND: Cinnabaris (α-HgS), a mineral traditional Chinese material medica, has been used in combination with other herbs manifesting some definite therapeutic effects for thousands of years. But the currently reported mercury poisoning incidents raised the doubts about the safety of Cinnabaris-containing traditional Chinese medicines (TCMs). Baizi Yangxin Pills (BZYXP) is a Cinnabaris-containing TCM widely used in clinical practice. This study evaluated the health risk of mercury exposure from BZYXP in healthy volunteers based on the total mercury and mercury species analysis of blood and urine after single and multiple doses of BZYXP. METHODS: Blood pharmacokinetics and urinary excretion studies of mercury were compared between single (9 g, once daily) and multiple doses (9 g, twice daily, continued for 7 days) of BZYXP. The whole blood and urine samples were collected at the specific points or periods after the administration of BZYXP. The total mercury and mercury species in blood and urine samples were determined by cold vapor-atomic fluorescence spectrometry (CV-AFS) and HPLC-CV-AFS, respectively. RESULTS: The mercury was excreted slowly and accumulated obviously after continuous exposure of BZYXP. Moreover, the well-known neurotoxin methylmercury (MeHg) was detected in blood samples after 7 days' administration of BZYXP. In the urine samples, only Hg(II) was detected. Therefore, long-term use of BZYXP will cause mercury poisoning due to mercury's high accumulative properties and MeHg formation. CONCLUSION: Cinnabaris-containing TCMs such as BZYXP should be restricted to cases in which alternatives are available, and the blood mercury species profile should be monitored during the long-term clinical medication.

Evaluation of pharmacological and pharmacokinetic herb-drug interaction between irinotecan hydrochloride injection and Kangai injection in colorectal tumor-bearing mice and healthy rats.

Introduction: Kangai (KA) injection, a Chinese herbal injection, is often used in combination with irinotecan (CPT-11) to enhance the effectiveness of anti-colorectal cancer treatment and alleviate side effects. However, the combined administration of this herb-drug pair remains controversial due to limited pre-clinical evidence and safety concerns. This study aimed to determine the pre-clinical herb-drug interactions between CPT-11 and KA injection to provide a reference for their clinical co-administration. Methods: In the pharmacological study, BALB/c mice with CT26 colorectal tumors were divided into four groups and treated with vehicle alone (0.9% saline), CPT-11 injection (100 mg/kg), KA injection (10 mL/kg), or a combination of CPT-11 and KA injection, respectively. The tumor volume of mice was monitored daily to evaluate the therapeutic effect. Daily body weight, survival rate, hematopoietic toxicity, immune organ indices, and gut toxicity were analyzed to study the adverse effects. Healthy Sprague-Dawley rats in the pharmacokinetic study were administered KA injection only (4 mL/kg), or a combination of CPT-11 injection (20 mg/kg) and KA injection, respectively. Six key components of KA injection (oxymatrine, matrine, ginsenoside Rb1, Rg1, Re, and astragaloside IV) in rat plasma samples collected within 24 h after administration were determined by LC-MS/MS. Results: The pharmacological study indicated that KA injection has the potential to enhance the anti-colorectal cancer efficacy of CPT-11 injection and alleviate the severe weight loss induced by CPT-11 injection in tumor-bearing mice. The pharmacokinetic study revealed that co-administration resulted in inhibition of oxymatrine metabolism in rats, evidenced by the significantly reduced Cmax and AUC0-t of its metabolite, matrine (p < 0.05), from 2.23 ± 0.24 to 1.38 ± 0.12 µg/mL and 8.29 ± 1.34 to 5.30 ± 0.79 µg h/mL, respectively. However, due to the similar efficacy of oxymatrine and matrine, this may not compromise the anti-cancer effect of this herb-drug pair. Discussion: This study clarified the pre-clinical pharmacology and pharmacokinetic benefits and risks of the CPT-11-KA combination and provided a reference for their clinical co-administration.

Gemcitabine enhances pharmacokinetic exposure of the major components of Danggui Buxue Decoction in rat via the promotion of intestinal permeability and down-regulation of CYP3A for combination treatment of non-small cell lung cancer.

CONTEXT: Danggui Buxue Decoction (DBD), a traditional Chinese medicine formula, has the potential to enhance the antitumor effect of gemcitabine in non-small cell lung cancer (NSCLC) treatment by increasing gemcitabine's active metabolites. However, whether gemcitabine affects the pharmacokinetics of DBD's major components remains unclear. OBJECTIVE: This study evaluates the herb-drug interaction between DBD's major components and gemcitabine and validates the underlying pharmacokinetic mechanism. MATERIALS AND METHODS: The pharmacokinetics of 3.6 g/kg DBD with and without a single-dose administration of 50 mg/kg gemcitabine was investigated in Sprague-Dawley rats. The effects of gemcitabine on intestinal permeability, hepatic microsomal enzymes in rat tissues, and CYP3A overexpressing HepG2 cells were determined using western blot analysis. RESULTS: The combination of gemcitabine significantly altered the pharmacokinetic profiles of DBD's major components in rats. The Cmax and AUC of calycosin-7-O-ß-d-glucoside notably increased through sodium-glucose transporter 1 (SGLT-1) expression promotion. The AUC of ligustilide and ferulic acid was also significantly elevated with the elimination half-life (t1/2) prolonged by 2.4-fold and 7.8-fold, respectively, by down-regulating hepatic CYP3A, tight junction proteins zonula occludens-1 (ZO-1) and occludin expression. DISCUSSION AND CONCLUSIONS: Gemcitabine could modulate the pharmacokinetics of DBD's major components by increasing intestinal permeability, enhancing transporter expression, and down-regulating CYP3A. These findings provide critical information for clinical research on DBD as an adjuvant for NSCLC with gemcitabine and help make potential dosage adjustments more scientifically and rationally.

Crude polysaccharide from Danggui Buxue decoction enhanced the anti-tumor effect of gemcitabine by remodeling tumor-associated macrophages.

Tumor-associated macrophages (TAMs) with an M2-phenotype mediate gemcitabine resistance to cancer by influencing the metabolic enzymes of gemcitabine and releasing competitive deoxycytidine (dC). Our previous studies showed that Danggui Buxue Decoction (DBD), a traditional Chinese medicinal recipe, enhances the anti-tumor activity of gemcitabine in vivo and alleviates gemcitabine-induced myelosuppression. However, the material basis and exact mechanism underlying its enhanced effects remain unclear. In this study, a bioactive polysaccharide consisting of arabinose, mannose, ribose, and glucose was isolated from DBD. In vivo results demonstrated that DBD crude polysaccharide (DBDP) ameliorated gemcitabine-induced immune system disorders. Moreover, DBDP improved the sensitivity of Lewis lung carcinoma-bearing mice to gemcitabine by reshaping the tumor-promoting M2-like macrophages into tumor-inhibiting M1-phenotypes. Furthermore, in vitro results further revealed that DBDP blocked the protective effects of TAMs and M2-macrophages against gemcitabine by inhibiting the excessive secretion of dC and decreasing the high expression of cytidine deaminase. In conclusion, our results demonstrated that DBDP, as the pharmacodynamic material basis of DBD, enhanced the anti-tumor activity of gemcitabine against lung cancer in vitro and in vivo, which was associated with remodeling of the M2-phenotype.

Pharmacovigilance of Herb-Drug Interactions: A Pharmacokinetic Study on the Combined Administration of Tripterygium Glycosides Tablets and Leflunomide Tablets in Rats by LC-MS/MS.

A popular and widely used combination therapy of leflunomide (LEF) and Tripterygium glycosides tablets (TGTS) has become a valuable clinical tool in China for the treatment of rheumatoid arthritis. This regimen has not been evaluated either in terms of interaction or toxicity, even given the rising concerns about LEF's prolonged elimination half-life and TGT's narrow therapeutic index, in addition to the current trend of using high doses of LEF. Thus, this study determines the potential adverse drug reactions between these two medicines. Reliable validated LC-MS/MS methods were used for the determination of teriflunomide (TER, the only active metabolite of LEF), and the main components of TGT: wilforlide A, wilforgine, wilfortrine, wilfordine, and wilforine. The results obtained from this investigation, as paralleled with the control groups, revealed that the Cmax and AUC0-t of TER were significantly decreased with separate co-administration, as the Cmax and AUC0-t were 30.17 ± 1.55 µg/mL and 24.47 ± 2.50 µg/mL, 374.55 ± 15.54 µg h/mL and 336.94 ± 21.19 µg h/mL, respectively (p < 0.05). Meanwhile, the pharmacokinetic profiles of the main components of TGT have also been affected by separate co-administration in rats. Therefore, herb−drug interactions between LEF and TGT have been proven.

Assessment of polybrominated diphenyl ethers and emerging brominated flame retardants in Pheretima (a Traditional Chinese Medicine): Occurrence, residue profiles, and potential health risks.

China produces and consumes large quantities of brominated flame retardants (BFRs) as well as several other unregulated electronic waste recycling activities, causing high BFR concentrations in the natural environment. Thus, Traditional Chinese Medicines (TCMs) may be contaminated by legacy BFRs (e.g. polybrominated diphenyl ethers (PBDEs)) and emerging BFRs (eBFRs, such as decabromodiphenyl ethane (DBDPE)) during growth, processing, packaging, and transportation. Pheretima, which is a typical animal drug recorded in Chinese Pharmacopoeia, was used as an example to evaluate human exposure to BFRs through TCM intake. This study is the first to determine 25 PBDEs and 5 eBFRs in Pheretima and estimate the daily BFR intake via Pheretima-containing TCMs. Twenty-seven Shanghai Pheretima and fifty-one Guang Pheretima samples were collected between March and June 2019 in southeast China. High BFR detection frequencies were found in Pheretima, of which BDE-209 and DBDPE were the most predominant analytes. The total PBDE contents ranged from 73 pg/g to 8,725 pg/g, while that of the eBFRs varied between 115 pg/g and 2,824 pg/g. The profiles and abundances were found to be species- and origin-dependent. However, the traditional processing of Pheretima may reduce BFR residues. Based on the usual clinical doses of Pheretima and the available chronic oral reference doses of BDE-47, 99, 153, and 209, the mean (95th percentile) of the total hazard quotient was estimated to be 9.1 × 10-5 (2.7 × 10-4). Therefore, there is little risk related to BFR exposure for patients taking formulated Pheretima-containing TCMs. However, it is necessary to establish routine monitoring programs for the co-existence of pollutants in TCMs to perform a systematic and comprehensive risk assessment.

Danggui Buxue Decoction enhances the anticancer activity of gemcitabine and alleviates gemcitabine-induced myelosuppression.

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue Decoction (DBD) as a traditional Chinese medicine (TCM) has been widely used to treat blood deficiency. With the immune regulation and hematopoietic effect, DBD improved the quality of life in non-small-cell lung cancer (NSCLC) patients. We previously reported that DBD sensitized the response of NSCLC to Gemcitabine (Gem); however, the synergism and attenuation mechanism on the combination of Gem and DBD has not yet been elucidated. AIM OF THE STUDY: To investigate the mechanisms of DBD in enhancing the anticancer activity of Gem and alleviating Gem-induced myelosuppression. MATERIALS AND METHODS: A549 nude mice model was established to study the effect on the combination of Gem and DBD. The organ indices, peripheral blood cells and the hematopoiesis-related cytokines were analyzed in Gem-induced myelosuppressive mice. Then we studied the whole process from Gem-induced bone marrow suppression to self-healing, and the mechanism of DBD's attenuation by the experiments of bone marrow nucleated cells (BMNCs). RESULTS: There were an enhanced anticancer effect and an improvement of hematopoietic function by combining of Gem and DBD in A549 nude mice model. DBD regulated Hu antigen R (HuR), deoxycytidine kinase (dCK) and nuclear factor erythroid 2-related factor (Nrf2), increased the expression of thrombopoietin (TPO) and granulocyte-macrophage colony stimulating factor (GM-CSF). For Gem-induced myelosuppressive mice, DBD improved the number of peripheral blood cells and the levels of hematopoiesis-related cytokines. Moreover, DBD was observed to reduce deoxyribonucleic acid (DNA) content at the G1 phase, promoted BMNCs proliferation and up-regulated cycle-related proteins. CONCLUSIONS: The results indicated that DBD not only improved the sensitivity of Gem but also alleviated Gem-induced myelosuppression. This study may provide a pharmacological basis for the combination of DBD and Gem in clinical application.

Arsenic-Related Health Risk Assessment of Realgar-Containing NiuHuangJieDu Tablets in Healthy Volunteers Po Administration.

Realgar, an arsenic-containing traditional Chinese medicine of As2S2, has significant therapeutic effects for hundreds of years. NiuHuangJieDu tablets (NHJDT) is one of the most commonly prescribed realgar-containing preparations for the treatment of sore throat, swelling, and aching of gums. However, realgar-containing TCMs raise great safety concerns due to the adverse effects reported by arsenic poisoning. In this study, the arsenic-related health risk assessment of NHJDT was conducted in healthy volunteers after single and multiple doses oral administration. Blood, plasma, and urine samples were collected after dosing at predetermined time points or periods. Simple, rapid, and sensitive methods were established for the quantification of total arsenic and arsenic speciation in biological samples. The total arsenic and arsenic speciation were determined by hydride generation-atomic fluorescence spectrometry (HG-AFS) and high-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS), respectively. No significant fluctuation of total arsenic was observed in human blood, and no traces of arsenic speciation were found in human plasma. Dimethylarsenic acid was detected as the predominated arsenic species in human urine after dosing. Therapeutic dose administration of NHJDT was relatively safe in single dose for the limited blood arsenic exposure, but long-term medication may still pose health risks due to the accumulation of arsenics in blood and its extremely slow excretion rate. Therefore, arsenic exposure should be carefully monitored during realgar-containing TCM medication, especially for long-term regimen. The results obtained in this study will provide scientific references for the clinical application of realgar and its-containing TCMs.

Pharmacovigilance of herb-drug interactions: A pharmacokinetic study on the combination administration of herbal Kang'ai injection and chemotherapy irinotecan hydrochloride injection by LC-MS/MS.

Chinese herbal drugs are often combined with chemotherapy drugs for the treatment of cancers. However, the combination administrations often do not have scientifically sound bases established on full preclinical and clinical investigations. A commonly used anti-colon-cancer herb-drug pair, irinotecan (CPT-11) hydrochloride injection and Kang'ai (KA) injection was taken as an example to investigate the possible pharmacokinetic interactions between Chinese herbal drugs and chemotherapy injections to determine the potential adverse drug reactions (ADRs). Rats were randomly divided into three groups and received 20 mg/kg CPT-11 injection 15 min after administration of 4 mL/kg saline for the CPT-11 single administration group and 4 mL/kg KA injection for the separated co-administration group, respectively. In the pre-mixed co-administration group, rats received a mixture of 20 mg/kg CPT-11 injection and 4 mL/kg KA injection. Blood samples were collected at 10 pre-determined time points between 0 and 24 h. The tissue samples were collected at 5 and 8 min after the injections, respectively. A reliable LC-MS/MS method was established for the simultaneous determination of CPT-11 and its metabolites, SN-38, SN-38 G and APC in the rat plasma and tissue samples, after full confirmation of two injections chemical and stability compatibilities. Compared to the C0 (5129 ± 757 ng/mL) and AUC0-t (7858 ± 1307 ng h/mL) of CPT-11 in the CPT-11 single administration group, the C0 (4574 ± 371 ng/mL) and AUC0-t (8779 ± 601 ng h/mL) after the separated co-administration remained unchanged, but the pre-mixed co-administration resulted with a significant increased C0 (29,454 ± 12,080 ng/mL) and AUC0-t (15,539 ± 5165 ng h/mL) (p < 0.05). Since the exposures of CPT-11 in most tissues in the pre-mixed co-administration group were dramatically lower than the separated co-administration group, the increased CPT-11 plasma concentration may be produced by the delayed tissue distribution because of the encapsulation by the components contained in KA injection, such as polysaccharides. Similar differences were also found in its metabolite, SN-38 G. There are obvious herb-drug interactions between CPT-11 injection and KA injection after the pre-mixed co-administration. The resulting excessive CPT-11 in the plasma may lead to many serious ADRs. Therefore, the full evaluation of herb-drug interactions is necessary and inappropriate combinations should be avoided.

Comparative health risk assessment of realgar and NiuHuangJieDu tablets based on tissue arsenic levels after multiple oral administration to rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Realgar (As2S2), a mineral traditional Chinese medicine (TCM), is proved to have great therapeutic effects in clinic and has been widely used in China for hundreds of years. As one of the most popular realgar-containing TCMs, NiuHuangJieDu Tablets (NHJDT) is used as OTC (over-the-counter) drug in daily life for fever relieving, detoxicating, as well as cure of sore throat and gingival swelling. However, the safety of realgar and its-containing TCMs still remains unclear. AIM OF THE STUDY: This study was to investigate the accumulation of arsenic in rat body and evaluate the safety of realgar-containing TCMs in vivo. MATERIALS AND METHODS: The health risk of arsenic was evaluated in rats by tissue distribution and histopathology, as well as arsenic speciation in plasma after multiple oral gavage of low and high doses of realgar and NiuHuangJieDu Tablets (NHJDT), respectively. Total arsenic and arsenic speciation were determined by hydride generation-atomic fluorescence spectrometry (HG-AFS) and high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS), respectively. RESULTS: Arsenic accumulated in rat tissues especially in heart, liver, spleen, lung, kidney, uterus and ovary. Dimethylarsenic acid (DMA) was detected as the predominant species in rat plasma after dosing. In comparison of realgar, NHJDT with co-existing components significantly alleviated tissues injury, and reduced arsenic concentration in rat tissues and plasma. CONCLUSIONS: NHJDT with co-existing components combination was relatively safer than realgar, but the accumulation of arsenic was still significant after long-term medication. Therefore, great attentions should be paid to realgar-containing TCMs to avoid toxicity from arsenic accumulation. Moreover, the dose regimen of realgar-containing TCMs should be designed rationally for clinical application. These results may provide useful references for the application of realgar-containing TCMs and might be helpful for the understanding of TCM compound compatibility.

Toxicity and risk assessment of mercury exposures from cinnabar and Baizi Yangxin Pills based on pharmacokinetic and tissue distribution studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Baizi Yangxin Pills (BZYXP), a popular cinnabar (α-HgS) contained Traditional Chinese Medicines (TCMs) is widely used in clinical trials. However, mercury is one of the most toxic elements. The adverse effects of cinnabar-containing TCMs have been occasionally reported in recent years, leading to the growing concerns about their toxicity and safety. AIM OF THE STUDY: The health risks of BZYXP and cinnabar related to the mercury exposures were evaluated through blood pharmacokinetic and tissue distribution studies in rats. MATERIALS AND METHODS: The distribution of absorbed mercury in rats' blood and tissues were measured by the developed cold-vapor atomic fluorescence spectrometric method. And the tissue damages were determined through the histopathological examinations. For single dose study, the low and high oral doses were equivalent to 1 and 10-fold therapeutic dose, respectively. The multiple doses study was conducted at low and high dose levels every 12 h for 30 consecutive days. RESULTS: Significant differences of mercury blood pharmacokinetic and tissue distribution characteristics were observed between the corresponding BZYXP and cinnabar groups. The herbal ingredients in BZYXP promoted the absorption of bio-accessible mercury of cinnabar and prolonged the elimination process, posing potential health risks. Although mercury was found easily accumulated in kidney, liver and brain tissues, kidney and liver didn't show obvious damages even after 30 days consecutive administration of BZYXP or cinnabar at 10-fold clinically equivalent doses. But brain did show some histopathological changes, and autonomic activities of rats decreased, pointing the potential neurotoxicity. CONCLUSIONS: Mercury tend to be accumulated especially when over-dose or prolonged medication with cinnabar-containing TCMs are given. The mercury exposures even at therapeutic doses of BZYXP or cinnabar do pose health risks from the neurotoxicity point of view.

Danggui Buxue Decoction Sensitizes the Response of Non-Small-Cell Lung Cancer to Gemcitabine via Regulating Deoxycytidine Kinase and P-glycoprotein.

This study aimed to investigate whether the anti-tumor effect of gemcitabine (GEM) in non-small-cell lung cancer (NSCLC) treatment was affected by Danggui Buxue decoction (DBD), and explore the potential mechanisms. The combined use of GEM and DBD showed an enhanced tumor growth inhibition effect in a murine Lewis lung carcinoma (LLC) model. LC-MS/MS results showed that the pharmacokinetic behaviors of a GEM active metabolite, gemcitabine triphosphate (dFdCTP), were found to be altered remarkably in the peripheral blood mononuclear cells (PBMC) of DBD co-administration rats. In addition, after co-administration of DBD with GEM, Western Blot and qPCR results confirmed that the expression of deoxycytidine kinase (dCK) in tumor tissues of LLC-bearing mice were markedly increased. DBD co-administration also reversed the upregulation of P-glycoprotein (P-gp) in tumor tissues induced by GEM. Moreover, DBD could notably up-regulate the IL-12p70 and GM-CSF expression in mice serum, suggesting potential immunomodulatory activities in tumor-bearing mice. Meanwhile, DBD inhibited the P-gp efflux activity in A549 cells. Therefore, the regulation of dCK and P-gp played important roles in the alternation of GEM pharmacokinetics and the enhancement of the anti-tumor effect of GEM. DBD being a potential dCK promoter could work as an adjuvant agent to boost the anticancer effect of GEM.

[Determination of 25 preservatives in cosmetics by gas chromatography-tandem mass spectrometry].

A method was developed for the simultaneous determination of benzoic acid and its esters, parabens, phenoxyisopropanol, chlorphenesin, dehydroacetic acid, 2,6-di-tert-butyl-4-methylphenol, methylchloroisothiazolone, methylisothiazolone and other preservatives in cosmetics by gas chromatography-tandem mass spectrometry (GC-MS/MS). The samples were extracted ultrasonically with a 0.1 mg/mL L(+)-ascorbic acid menthol solution after being spiked with a mixture solution of 2-octanol, phenol and heptachlor as internal standards and anhydrous sodium sulfate as a dehydrating reagent. Finally, the extract was centrifuged, filtered, and then analyzed by GC-MS/MS. The analytes were separated using an HP-5MS capillary column (30 m×0.25 mm×0.25 µm) with a temperature-programming program. The inlet, transfer line and ion source temperatures were set to 260, 250 and 230℃, respectively. Helium (99.999%) was used as the carrier gas at a flow rate of 1 mL/min. The final extract (1 µL) was injected in split mode (10:1). Analysis was performed in the multiple reaction monitoring (MRM) mode. Three types of cosmetics, as well as water, milk and cream as samples were selected to verify the accuracy of the method at four levels. The average spiked recoveries ranged from 82.3% to 119.4% with relative standard deviations (n=6) of less than 14.3%. The limits of detection were lower than 0.99 µg/kg for all the preservatives. The method is sensitive, and reliable for the simultaneous determination of the 25 preservatives in cosmetics. Nonetheless, complementary methods need to be developed for the determination of some other preservatives that cannot be detected by GC-MS/MS.

Health risk assessment of arsenic in Realgar and NiuHuangJieDu Tablets based on pharmacokinetic study.

NiuHuangJieDu Tablets (NHJDT), a popular realgar (As4S4) containing patented traditional Chinese medicine (TCM), is widely used in the treatment of acute tonsillitis, pharyngitis, periodontitis and mouth ulcer. However, arsenic is considered as one of the most toxic elements, leading to growing concerns about the quality and safety of realgar-containing TCMs recently. In this study, health risk assessment of arsenic in realgar and NHJDT was conducted through oral administration of both substances to rats with single and multiple doses, respectively. The total blood arsenic concentration was used as the health risk indicator and determined by hydride generation-atomic fluorescence spectrometry after modified Kjeldahl digestion, and then applied to the pharmacokinetic study. For single oral dose study in rats, the low, medium, and high doses of realgar and NHJDT were set equivalent to 1, 5 and 20 times the human therapeutic dose (1.3 mg realgar/kg), respectively. Multiple doses were given at low and high dose levels every 12 h for seven consecutive days, respectively. Significant differences in the total blood arsenic pharmacokinetic profiles were observed between the corresponding realgar and NHJDT groups. These results indicated that NHJDT significantly reduced the total blood arsenic exposure present in realgar, and the detoxification mechanism might be attributed to herb-herb interactions in NHJDT. However, the accumulation of blood total arsenic was significant due to the long elimination half-life and high accumulation index in both realgar and NHJDT groups. Therefore, the potential health risk of arsenic caused by the administration of realgar-containing TCMs should be taken into account for excessive or long-term medication. Precautions should be taken for the clinical application of realgar-containing TCMs.

[Pharmacokinetics of mercury after oral administration of cinnabaris and Fufang Niuhuang Xiaoyan capsule in rats].

Fufang Niuhuang Xiaoyan capsule was a classical compound prescription with the efficacy of heat-clearing, detoxification, sedation and anti-inflammation, with cinnabaris as one of its active ingredients. The study focuses on the pharmacokinetics of mercury in rats after oral administration of cinnabaris and Fufang Niuhuang Xiaoyan capsule, in order to explore the effect of combined traditional Chinese medicines on mercury metabolism. In this study, the method of nitric-perchloric acid digestion system coupled with cold atomic-atomic fluorescence spectroscopy (CV-AFS) was adopted to accurately determine mercury in whole blood of rats. Fufang Niuhueng Xiaoyan capsule had three dose schemes of oral administration, namely equivalent clinical dose, 3 times of equivalent clinical dose and 10 times of equivalent clinical dose; And the doses of oral administration of cinnabaris was calculated according to that of Fufang Niuhuang Xiaoyan capsule. SPF grade healthy SD rats were fasted overnight before the oral administration with cinnabaris suspension (or Fufang Niuhuang Xiaoyan capsule suspension). After oral administration of different doses of cinnabaris, no obvious changes in tmax and MRT were observed, while Cmax/dose, AUC0-48 h/dose and AUC0-∞/dose decreased with the increase in dose, indicating that total mercury absorption in body was declining. As the dose increased, Ke, CL/F decreased, and t1/2 increased, indicating that the elimination slowed down, and mercury metabolism showed non-linear dynamic characteristics within a certain range of dose (22-220 mg•kg⁻¹). The total mercury metabolism in the whole blood of rats after oral administration with different doses of Fufang Niuhuang Xiaoyan capsule also showed non-linear dynamic characteristics. The results were correlated with the low solubility of cinnabaris in the body. Compared with cinnabaris, Fufang Niuhuang Xiaoyan capsule showed no obvious changes in V/F and MRT, while Ke, CL/F, tmax decreased, and t1/2, Cmax/dose, AUC0-48 h/dose, AUC0-∞/dose increased significantly. The results showed that Fufang Niuhuang Xiaoyan capsule accelerated absorption, slowed down elimination and improved the total absorption of mercury in the whole blood, indicating that Fufang Niuhuang Xiaoyan capsule may contain components for promoting absorption and alleviating elimination of mercury. Fufang Niuhuang Xiaoyan capsule had an impact on the pharmacokinetics of cinnabaris, and long-term administration of cinnabaris (Fufang Niuhuang Xiaoyan capsule) was possible to cause accumulation of mercury in the body. This study could explain changes in efficacy of Fufang Niuhuang Xiaoyan capsule, evaluate the rationality of compound medicines containing toxic elements and provide scientific basis for the rational and safe use of Fufang Niuhuang Xiaoyan capsule.

Bioaccessibility and health risk assessment of mercury in cinnabar containing Traditional Chinese Medicines.

Cinnabar (α-HgS), has been formulated in Traditional Chinese Medicines (TCMs) for thousands of years. Since the total Hg content was accepted widely as the toxicity criteria, the safety alerts have been issued about the cinnabar containing TCMs for exceeding Hg limits. However, cinnabar is almost insoluble in water, the oral absorption is extremely low. Hence, it is not suitable to use the total Hg content alone to evaluate the toxicity of cinnabar containing TCMs. In instead, the bioaccessible Hg is a much reasonable safety indicator. In this study, bioaccessible Hg contents of 29 cinnabar containing TCMs were determined by cold vapor-atomic fluorescence spectrometry after in vitro extractions with the simulated gastrointestinal fluids, while the total Hg contents were determined after acid digestion. According to the daily dosages, the bioaccessible Hg exposures of these TCMs were evaluated, and most of them were within the permitted daily exposure set by the International Council for Harmonisation, demonstrating that these TCMs are safe when administrated following the instructions. However, the obtained results also suggested that the Hg exposure could also be influenced by the herbal ingredients in TCMs and the bioactivities in gastrointestinal tract, indicating the possible health risks after excessive or long-term medication of cinnabar containing TCMs. Considering the influencing factors of the Hg intakes after oral administration of cinnabar containing TCMs, the bioaccessible Hg exposure should be considered as a more rational criterion for evaluating the health risks than the total Hg content. Furthermore, precautions should also be taken to ensure safe usages of cinnabar containing TCMs from both the cinnabar contents and the processing procedures points of view, as well as the daily dosage regimen, for all of them are directly related with the bioaccessible Hg exposures.

Simultaneous LC-MS/MS determination of five tripterygium pyridine alkaloids in dog plasma and its application to their pharmacokinetic study after oral administration of tripterygium glycosides tablets.

A sensitive and selective liquid chromatography tandem mass spectrometric method was developed and validated for the simultaneous determination of five pyridine alkaloids contained in tripterygium glycosides tablets (triptolide, wilforine, wilforgine, wilfording and wilfortrine) in dog plasma. The analysis was carried out on a Sepax GP-Phenyl column using a mixture of methanol and 10mmol/L ammonium formate buffer solution containing 0.1% formic acid (75:25, v/v) as the mobile phase pumped at a flow-rate of 1.0mL/min. All MS data were obtained in the positive ESI mode with selective multiple reaction monitoring of ion transitions. The method was fully validated to be accurate and precise with a linear range of 0.2-1000ng/mL for triptolide and 0.05-1000ng/mL for the other four pyridine alkaloids. The intra-day and inter-day precisions (relative standard deviation, RSD, %) were within 10.6% and 14.0%, respectively, and the relative error (RE, %) were all less than 13.1%. The method was successfully applied to multi-components pharmacokinetic study of the five pyridine alkaloids in beagle dogs after a single oral administration of 3mg/kg and 30mg/kg tripterygium glycosides tablets, respectively, and a multiple oral administration of 30mg/kg for 6 consecutive days.

Rapid and sensitive analysis of multiple bioactive constituents in tripterygium glycosides tablets using liquid chromatography coupled with time-of-flight mass spectrometry.

A simultaneous determination method based on liquid chromatography coupled with time-of-flight mass spectrometry was developed for the analysis of 11 bioactive constituents in tripterygium glycosides tablets, an immune and inflammatory prescription used in China. The analysis was fully optimized on a 1.8 µm particle size C18 column with linear gradient elution, permitting good separation of the 11 analytes and two internal standards in 21 min. The quantitation of each target constituent was carried out using the narrow window extracted ion chromatograms with a ±l0 ppm extraction window, yielding good linearity (r(2) > 0.996) with a linear range of 10-1000 ng/mL. The limits of quantitation were low ranging from 0.25 to 5.02 ng/mL for the 11 analytes, and the precisions and repeatability were better than 1.6 and 5.3%, respectively. The acceptable recoveries obtained were in the range of 93.4-107.4%. This proposed method was successfully applied to quantify the 11 bioactive constituents in commercial samples produced by nine pharmaceutical manufacturers to profile the quality of these preparations. The overall results demonstrate that the contents of the 11 bioactive constituents in different samples were in great diversity, therefore, the quality, clinical safety, and efficacy of this drug needs further research and evaluation.

Impact on L-carnitine Homeostasis of Short-term Treatment with the Pivalate Prodrug Tenofovir Dipivoxil.

Pivalate-generating prodrugs have been suggested to cause clinically significant hypocarnitinaemia. Tenofovir dipivoxil, a novel ester prodrug of tenofovir, can be used for treatment for hepatitis B and HIV infection and it was necessary to evaluate the effect of its treatment on carnitine homeostasis. We sought to investigate the effect of Class 1 drug tenofovir dipivoxil on endogenous L-carnitine level during a 72-hr test in healthy Chinese volunteers and to establish a suitable dose of L-carnitine nutritional supplement for patients who were administered short-term tenofovir dipivoxil tablets for treatment for hepatitis B and herpes simplex virus infection. Tenofovir dipivoxil was administered in one of eight dosing regimens (single dose 150, 300 and 600 mg, multiple dose 300, 450, and 600 mg, multiple dose 450 (600) mg tenofovir dipivoxil and 0.5 g L-carnitine) to gender-balanced groups of 84 healthy Chinese volunteers. Plasma concentrations of L-carnitine were quantified before, during and after treatment. Plasma L-carnitine concentrations fell during tenofovir dipivoxil dosing. The nadir in L-carnitine concentration was dependent on the dose of tenofovir dipivoxil and it decreased from 6.1 ± 0.6 to 4.4 ± 0.8 µg/ml, 6.1 ± 1.8 to 3.3 ± 1.2 µg/ml, 6.2 ± 0.6 to 2.5 ± 0.5 µg/ml for single doses of 150, 300, 600 mg tenofovir dipivoxil tablets and from 6.0 ± 1.4 to 2.1 ± 1.5 µg/ml, 6.2 ± 0.4 to 0.9 ± 0.5 µg/ml for multiple doses of 450, 600 mg tenofovir dipivoxil tablets, respectively. Short-term administration of tenofovir dipivoxil results in hypocarnitinaemia and increased losses of carnitine in resulting of minor adverse events of decreased food appetite, nausea, abdominal distention and muscle weakness.

Liquid chromatography-hydride generation-atomic fluorescence spectrometry determination of arsenic species in dog plasma and its application to a pharmacokinetic study after oral administration of Realgar and Niu Huang Jie Du Pian.

A high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) method was developed for the simultaneous determination of four arsenic species (As(III), dimethylarsinic acid (DMA), monomethylarsonic acid (MMA) and arsenate As(V)) in dog plasma. Good separation of the four arsenic species was achieved within 15min on an anion-exchange column with isocratic elution using 15mmol/L KH(2)PO(4) (pH 5.9) as eluent at a flow rate of 1.0mL/min. The assay was linear over the range of 1.25-200, 1.56-200, 1.34-172, and 2.50-200ng/mL with the detection limits of 0.80, 1.00, 0.86 and 2.00ng/mL for As(III), DMA, MMA and As(V), respectively. The method was validated for selectivity, precision, accuracy and recovery and then applied to a comparative pharmacokinetic study of the arsenic species in beagle dogs after a single oral administration of Realgar (24.32mg/kg, equivalent to 11.31mgAs/kg) alone or Niu Huang Jie Du Pian (a patent traditional Chinese medicine (TCM), 380mg/kg, equivalent to 28.45mgAs/kg), respectively. DMA was found to be the predominant species in the dog plasma after dosing, with As(V) appeared as the quickly eliminating one. No traces of MMA and As(III) were detected at any sampling time points. The main pharmacokinetic parameters found for DMA p.o. administration of Realgar and Niu Huang Jie Du Pian were as follows: C(max) (14.7±4.2) and (57.0±32.0)ng/mL, T(max) (2.4±0.5) and (2.5±0.5)h, AUC(0-36) (151.1±12.9) and (635.9±418.2)ngh/mL, AUC(0-∞) (206.0±44.5) and (687.2±425.1)ngh/mL, t(1/2) (16.2±7.9) and (9.4±2.2)h, respectively. The influence of compounding in Niu Huang Jie Du Pian on the pharmacokinetics of arsenics was shown with increased transformation of DMA and its faster elimination rate.