Yan Yi1, Shuangrong Gao1, Jing Xia2, Chunying Li1, Yong Zhao1, Yushi Zhang1, Aihua Liang3, Shen Ji4. 1. Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medicial Sciences, 16 Nanxiaojie, Dongzhimen Nei, Beijing, 100700, China. 2. Shanghai Institute for Food and Drug Control, No. 1500 Shanghai Zhang Heng Road, Pudong New District, Shanghai, 201203, China. 3. Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medicial Sciences, 16 Nanxiaojie, Dongzhimen Nei, Beijing, 100700, China. Electronic address: ahliang@icmm.ac.cn. 4. Shanghai Institute for Food and Drug Control, No. 1500 Shanghai Zhang Heng Road, Pudong New District, Shanghai, 201203, China. Electronic address: jishen2013@163.com.
Abstract
AIM OF THE STUDY: Because the toxicity and efficacy of arsenic is closely related to its chemical species, we conducted examinations of arsenic species accumulation and distribution in the rat body after one-time and 30-day realgar administration and then elucidated the probable roles of different arsenic species in the short-term toxicity of realgar. MATERIALS AND METHODS: According to ICH M3 guidelines for non-clinical repeated dose toxicity studies and OECD Test guideline TG407 "Repeated Dose 28-Day oral Toxicity Study in Rodents, the doses of realgar set were 10.6 mg/kg, 40.5 mg/kg and 170 mg/kg. Rats were orally administered with realgar for one-tme and 30 days, respectively. Thereafter, biological samples (plasma, urine, liver, kidney, and brain) were obtained from rats and analyzed using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) to determine realgar metabolism, arsenic species accumulation and distribution. Additionally, the toxicity of realgar in rats was evaluated. RESULTS: The absorption, distribution and elimination half-life of total arsenic species in realgar were 3.33 hs, 16.08 hs and 24.65 hs, respectively. After 30 days of oral administration of realgar in rats, no significant drug-related toxicity occurred in the rats. Dimethylarsenic acid (DMA) is the most abundant arsenic species. The DMA contents of the liver and kidney of the high-dose realgar group were approximately 40-fold and 50-fold higher than those in the corresponding tissues of the control group, respectively. The arsenic species (III) was mainly detected in the liver and its content was about 40-fold higher than that of the control group. MMA was mainly detected in rat kidney, and the MMA content of the realgar treatment group was more than 2000 times higher than that of the control group. CONCLUSIONS: Arsenic is rapidly absorbed and distributed over the liver, kidneys and brain, and the distribution and elimination of arsenic in the blood is slow. The realgar doses corresponded to human equivalent doses (HED) of 1.7, 6.4 and 27.2 mg/kg, respectively. Considering that humans are 10 times more sensitive than animals, the realgar dose is equivalent to 0.17, 0.64 and 2.7 mg/kg HED. It can be considered that if patients take no more than 2.7 mg/kg realgar for 2 weeks, there will be no adverse reactions.
AIM OF THE STUDY: Because the toxicity and efficacy of arsenic is closely related to its chemical species, we conducted examinations of arsenic species accumulation and distribution in the rat body after one-time and 30-day realgar administration and then elucidated the probable roles of different arsenic species in the short-term toxicity of realgar. MATERIALS AND METHODS: According to ICH M3 guidelines for non-clinical repeated dose toxicity studies and OECD Test guideline TG407 "Repeated Dose 28-Day oral Toxicity Study in Rodents, the doses of realgar set were 10.6 mg/kg, 40.5 mg/kg and 170 mg/kg. Rats were orally administered with realgar for one-tme and 30 days, respectively. Thereafter, biological samples (plasma, urine, liver, kidney, and brain) were obtained from rats and analyzed using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) to determine realgar metabolism, arsenic species accumulation and distribution. Additionally, the toxicity of realgar in rats was evaluated. RESULTS: The absorption, distribution and elimination half-life of total arsenic species in realgar were 3.33 hs, 16.08 hs and 24.65 hs, respectively. After 30 days of oral administration of realgar in rats, no significant drug-related toxicity occurred in the rats. Dimethylarsenic acid (DMA) is the most abundant arsenic species. The DMA contents of the liver and kidney of the high-dose realgar group were approximately 40-fold and 50-fold higher than those in the corresponding tissues of the control group, respectively. The arsenic species (III) was mainly detected in the liver and its content was about 40-fold higher than that of the control group. MMA was mainly detected in rat kidney, and the MMA content of the realgar treatment group was more than 2000 times higher than that of the control group. CONCLUSIONS:Arsenic is rapidly absorbed and distributed over the liver, kidneys and brain, and the distribution and elimination of arsenic in the blood is slow. The realgar doses corresponded to human equivalent doses (HED) of 1.7, 6.4 and 27.2 mg/kg, respectively. Considering that humans are 10 times more sensitive than animals, the realgar dose is equivalent to 0.17, 0.64 and 2.7 mg/kg HED. It can be considered that if patients take no more than 2.7 mg/kg realgar for 2 weeks, there will be no adverse reactions.
Authors: Sofia Navarro-Espinoza; Aracely Angulo-Molina; Diana Meza-Figueroa; Guillermo López-Cervantes; Mercedes Meza-Montenegro; Aurora Armienta; Diego Soto-Puebla; Erika Silva-Campa; Alexel Burgara-Estrella; Osiris Álvarez-Bajo; Martín Pedroza-Montero Journal: Int J Environ Res Public Health Date: 2021-01-19 Impact factor: 3.390
Authors: Xiao Wu; Ruoning Yan; Rong Guan; Yi Du; Yuexin Liu; Shanhu Wu; Song Zhu; Min Song; Taijun Hang Journal: Front Pharmacol Date: 2022-01-07 Impact factor: 5.810