药物安全评价用SD大鼠90 d喂养试验的背景数据研究

doi:10.12300/j.issn.1674-5817.2024.187

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (4): 439-448.DOI: 10.12300/j.issn.1674-5817.2024.187

药物安全评价用SD大鼠90 d喂养试验的背景数据研究

秦超, 李双星, 赵婷婷, 蒋晨晨, 赵晶, 杨艳伟, 林志, 王三龙, 文海若()()

中国食品药品检定研究院国家药物安全评价监测中心, 药物非临床安全评价研究北京市重点实验室, 北京 100176

收稿日期:2024-12-17 修回日期:2025-04-17 出版日期:2025-08-25 发布日期:2025-09-01
通讯作者: 文海若（1981—），女，博士，研究员，研究方向：药物安全性评价。E-mail： wenhairuo@nifdc.org.cn。ORCID： 0000-0002-7648-1088
作者简介:秦超（1983—），男，本科，主管技师，研究方向：动物实验技术。E-mail： 123642651@qq.com；
李双星（1995—），男，硕士，助理研究员，研究方向：毒性病理。E-mail： lishuangxing@nifdc.org.cn
基金资助:
国家科技重大专项“重大新药创制”专项课题“创新药物非临床安全性评价关键技术研究”(2018ZX09201-017);药品监管科学全国重点实验室课题“药品杂质遗传毒性评价新技术和生物标志物研究”(2023SKLDRS0128);中国食品药品检定研究院中青年发展研究基金课题“细胞治疗产品肿瘤杀伤的新型体外药效评价模型的建立及应用”(2023C1)

Study on the 90-day Feeding Experimental Background Data of SD Rats for Drug Safety Evaluation

QIN Chao, LI Shuangxing, ZHAO Tingting, JIANG Chenchen, ZHAO Jing, YANG Yanwei, LIN Zhi, WANG Sanlong, WEN Hairuo()()

National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Key Laboratory of Beijing for Nonclinical Safety Evaluation Research of Drugs, Beijing 100176, China

Received:2024-12-17 Revised:2025-04-17 Published:2025-08-25 Online:2025-09-01
Contact: WEN Hairuo (ORCID: 0000-0002-7648-1088), E-mail: wenhairuo@nifdc.org.cn

摘要/Abstract

摘要：

目的为保证研究数据的可靠性，建立SD大鼠90 d喂养试验的背景数据。方法汇总2020—2023年国家药物安全评价监测中心的6个独立的SD大鼠90 d喂养试验中空白对照组动物（120只SPF级4周龄SD大鼠，雌雄各半，仅给予普通鼠全价颗粒饲料）的背景数据。检疫期结束后，继续观察大鼠90 d，之后腹腔注射舒泰（50 mg/mL）麻醉、取血、处死并解剖。通过分析空白对照组数据，建立SD大鼠相关背景数据库。结果雄性和雌性大鼠的平均体重均稳步增长，雄性大鼠体重增长幅度更为明显。90 d内雄性和雌性大鼠平均体重分别增长至500 g和300 g以上。3周后，雄性大鼠每日平均摄食量基本稳定在25~28 g/只，雌性大鼠每日平均摄食量基本稳定在16~19 g/只。所有动物的食物利用率自实验第1周开始逐渐下降。白细胞分类计数结果中，雌性与雄性白细胞（white blood cell，WBC）、中性粒细胞（neutrophil，Neut）、淋巴细胞（lymphocyte，Lymph）、单核细胞（monocyte，Mono）的数值差异有统计学意义（P <0.001），但中性粒细胞百分率（neutrophil percentage，%Neut）、淋巴细胞百分率（lymphocyte percentage，%Lymph）、单核细胞百分率（monocyte percentage，%Mono）两性别之间差异无统计学意义（P >0.05）。雄性动物的平均红细胞数（red blood cell count，RBC）、血红蛋白浓度（hemoglobin，HGB）、红细胞比容（hematocrit，HCT）、血小板数（platelet count，PLT）、凝血酶原时间（prothrombin time，PT）和活化部分凝血激酶时间（activated partial thromboplastin time，APTT）高于雌性（P <0.05）。雄性大鼠平均丙氨酸氨基转移酶（alanine aminotransferase，ALT）、天门冬氨酸氨基转移酶（aspartate aminotransferase，AST）、碱性磷酸酶（alkaline phosphatase，ALP）、肌酸磷酸激酶（creatine phosphokinase，CK）、乳酸脱氢酶（lactate dehydrogenase，LDH）、葡萄糖（glucose，GLU）、甘油三酯（triglyceride，TG）数值显著高于雌性（P <0.05）。雄性动物的尿pH值在5.0~8.5，雌性动物尿pH值在6.5~9.0。绝大多数雄性动物的尿比重低于1.020，绝大多数雌性动物的尿比重低于1.015。雄性动物各脏器（肾上腺、生殖器官除外）质量均高于雌性（P <0.001），而雌性动物的脏体比（肾脏、生殖器官除外）高于雄性（P <0.001）。结论总结国家药物安全评价监测中心6项90 d喂养试验中未给药对照组SPF级SD大鼠的体重、摄食量、血液学、血清生化各项指标的背景参考值范围，可为相关研究提供重要的参考数据。梳理大鼠背景性和自发性的组织病理学改变，有助于后续研究的规范化和标准化，以及对异常结果的评判分析。

关键词: 药物安全评价, SD大鼠, 90 d喂养试验, 血液学, 血清生化, 病理学改变

Abstract:

Objective To establish background data for a 90-day feeding trial of SD rats to ensure the reliability of research data. Methods Background data from six independent 90-day feeding trials of SD rats conducted by the National Center for Safety Evaluation of Drugs from 2020 to 2023 were summarized. These studies involved a blank control group of 120 SPF-grade 4-week-old SD rats, with an equal number of males and females, which were only given standard full-nutrient pelleted rat feed. After the quarantine period, the animals were observed for an additional 90 days, followed by intraperitoneal injection of Zoletil (50 mg/mL) for anesthesia, blood sampling, euthanasia, and necropsy. By analyzing the data from the blank control group, a relevant background database for SD rats was established. Results Both male and female rats exhibited steady weight gain, with a more pronounced increase in male rats. Within 90 days, the average body weight of male and female rats increased to over 500 g and 300 g, respectively. Three weeks later, the average daily food intake of male rats stabilized at approximately 25~28 g per rat, while that of female rats remained stable at approximately 16~19 g per rat. The food utilization rate of all animals gradually decreased from the first week of the experiment. In the white blood cell (WBC) differential count results, significant differences were observed in the counts of WBCs, neutrophils (Neut), lymphocytes (Lymph), and monocytes (Mono) between males and females (P<0.001). However, there were no significant differences in the percentages of neutrophil (%Neut), lymphocyte (%Lymph), and monocyte (%Mono) between the sexes (P>0.05). The average red blood cell count (RBC), hemoglobin concentration (HGB), hematocrit (HCT), platelet count (PLT), prothrombin time (PT), and activated partial thromboplastin time (APTT) were higher in male animals than in female animals (P<0.05). The average values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatine phosphokinase (CK), lactate dehydrogenase (LDH), glucose (GLU), and triglyceride (TG) in male rats were higher than those in female rats (P<0.05). The urinary pH range for male animals was 5.0 to 8.5, while for female animals it was 6.5 to 9.0. The majority of male animals had a urinary specific gravity lower than 1.020, and the majority of female animals had a urinary specific gravity lower than 1.015. The weights of various organs (excluding the adrenal glands and reproductive organs) in male animals were heavier than those in female animals (P<0.001), while the organ/body weight ratios (excluding the kidneys and reproductive organs) of female animals were higher than those of male animals (P<0.001). Conclusion This study summarizes the background reference ranges for body weight, food intake, hematology, and serum biochemistry indicators in SPF-grade SD rats in the untreated control group from six 90-day feeding trials conducted by the National Center for Safety Evaluation of Drugs. It provides important reference data for related research. By summarizing the background and spontaneous histopathological changes in rats, this study aids in the standardization and normalization of subsequent research, as well as in the evaluation and analysis of abnormal results.

Key words: Drug safety evaluation, SD rats, 90-day feeding study, Hematology, Serum biochemistry, Pathological changes

中图分类号:

Q95-33

秦超,李双星,赵婷婷,等. 药物安全评价用SD大鼠90 d喂养试验的背景数据研究[J]. 实验动物与比较医学, 2025, 45(4): 439-448. DOI: 10.12300/j.issn.1674-5817.2024.187.

QIN Chao,LI Shuangxing,ZHAO Tingting,et al. Study on the 90-day Feeding Experimental Background Data of SD Rats for Drug Safety Evaluation[J]. Laboratory Animal and Comparative Medicine, 2025, 45(4): 439-448. DOI: 10.12300/j.issn.1674-5817.2024.187.

图/表 6

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指标 Index	雄性 Male	雌性 Female
WBC C_cell/(10⁹·L^-1)	7.36±4.27	4.82±3.06
%Neut /%	14.10±9.02	14.50±10.58
Neut C_cell/(10⁹·L^-1)	1.04±1.04	0.67±0.53
%Lymph /%	80.30±10.58	80.00±11.96
Lymph C_cell/(10⁹·L^-1)	5.90±3.35	3.89±2.76
%Mono /%	2.30±1.96	2.20±1.37
Mono C_cell/(10⁹·L^-1)	0.17±0.20	0.10±0.08
%Eos /%	1.50±0.98	1.70±1.37
Eos C_cell/(10⁹·L^-1)	0.11±0.08	0.08±0.06
%Baso /%	0.2±0.2	0.1±0.1
Baso C_cell/(10⁹·L^-1)	0.01±0.01	0.01±0.01
RBC C_cell/(10¹²·L^-1)	8.90±0.74	8.05±0.69
HGB ρ/(g·L^-1)	155±14	148±10
HCT /%	50.0±5.0	46.5±5.0
MCV /fL	56.2±4.1	57.7±4.5
MCH m/(pg)	17.4±1.4	18.4±1.2
MCHC ρ/(g·L^-1)	310±31	318±27
PLT C_cell/(10⁹·L^-1)	996±321	939±300
MPV /fL	8.2±3.7	8.3±2.9
%Retic /%	3.24±5.94	2.40±1.43
Retic C_cell/(10⁹·L^-1)	288.5±53.5	191.9±108.6
PT /s	10.7±5.7	8.5±0.8
APTT /s	16.9±5.5	12.8±3.9

指标 Index	雄性 Male	雌性 Female
WBC C_cell/(10⁹·L^-1)	7.36±4.27	4.82±3.06
%Neut /%	14.10±9.02	14.50±10.58
Neut C_cell/(10⁹·L^-1)	1.04±1.04	0.67±0.53
%Lymph /%	80.30±10.58	80.00±11.96
Lymph C_cell/(10⁹·L^-1)	5.90±3.35	3.89±2.76
%Mono /%	2.30±1.96	2.20±1.37
Mono C_cell/(10⁹·L^-1)	0.17±0.20	0.10±0.08
%Eos /%	1.50±0.98	1.70±1.37
Eos C_cell/(10⁹·L^-1)	0.11±0.08	0.08±0.06
%Baso /%	0.2±0.2	0.1±0.1
Baso C_cell/(10⁹·L^-1)	0.01±0.01	0.01±0.01
RBC C_cell/(10¹²·L^-1)	8.90±0.74	8.05±0.69
HGB ρ/(g·L^-1)	155±14	148±10
HCT /%	50.0±5.0	46.5±5.0
MCV /fL	56.2±4.1	57.7±4.5
MCH m/(pg)	17.4±1.4	18.4±1.2
MCHC ρ/(g·L^-1)	310±31	318±27
PLT C_cell/(10⁹·L^-1)	996±321	939±300
MPV /fL	8.2±3.7	8.3±2.9
%Retic /%	3.24±5.94	2.40±1.43
Retic C_cell/(10⁹·L^-1)	288.5±53.5	191.9±108.6
PT /s	10.7±5.7	8.5±0.8
APTT /s	16.9±5.5	12.8±3.9

指标 Index	雄性 Male	雌性 Female
ALT z/(U·L^-1)	37±18	28±16
AST z/(U·L^-1)	128±35	107±37
ALP z/(U·L^-1)	104±45	53±27
CK z/(U·L^-1)	747±494	634±439
LDH z/(U·L^-1)	1 240±735	1 072±672
GGT z/(U·L^-1)	4.52±1.84	2.43±0.88
TBIL c/(μmol·L^-1)	2.61±0.76	3.16±1.31
UREA c/(mmol·L^-1)	6.10±2.35	6.20±2.35
CRE c/(μmol·L^-1)	30±8	34±8
GLU c/(mmol·L^-1)	7.80±3.02	6.92±1.41
CHO c/(mmol·L^-1)	1.80±0.82	1.97±0.98
TG c/(mmol·L^-1)	0.68±0.53	0.56±0.51
TP ρ/(g·L^-1)	64.3±10.2	69.0±11.4
ALB ρ/(g·L^-1)	40.8±12.0	48.5±15.3
A/G	1.81±0.88	2.51±1.45
K⁺c/(mmol·L^-1)	5.04±0.61	4.61±0.61
Na⁺c/(mmol·L^-1)	144.1±3.3	143.1±2.5
Cl^-c/(mmol·L^-1)	102.9±4.3	103.4±5.3

指标 Index	雄性 Male	雌性 Female
ALT z/(U·L^-1)	37±18	28±16
AST z/(U·L^-1)	128±35	107±37
ALP z/(U·L^-1)	104±45	53±27
CK z/(U·L^-1)	747±494	634±439
LDH z/(U·L^-1)	1 240±735	1 072±672
GGT z/(U·L^-1)	4.52±1.84	2.43±0.88
TBIL c/(μmol·L^-1)	2.61±0.76	3.16±1.31
UREA c/(mmol·L^-1)	6.10±2.35	6.20±2.35
CRE c/(μmol·L^-1)	30±8	34±8
GLU c/(mmol·L^-1)	7.80±3.02	6.92±1.41
CHO c/(mmol·L^-1)	1.80±0.82	1.97±0.98
TG c/(mmol·L^-1)	0.68±0.53	0.56±0.51
TP ρ/(g·L^-1)	64.3±10.2	69.0±11.4
ALB ρ/(g·L^-1)	40.8±12.0	48.5±15.3
A/G	1.81±0.88	2.51±1.45
K⁺c/(mmol·L^-1)	5.04±0.61	4.61±0.61
Na⁺c/(mmol·L^-1)	144.1±3.3	143.1±2.5
Cl^-c/(mmol·L^-1)	102.9±4.3	103.4±5.3

性别 Gender	葡萄糖 Glucose	蛋白质 Protein	胆红素 Bilirubin	尿胆原 Urobilinogen	酸碱值 pH	尿比重 Urine specific gravity	隐血 Occult blood	酮体 Ketones	亚硝酸盐 Nitrite	白细胞 WBC C_cell/(10⁹·L^-1)
雄性 Male	-: 60/60	-: 1/60	-: 59/60	NORMAL: 41/60	5.0: 2/60	<1.005: 18/60	-: 41/60	-: 22/60	-: 60/60	-: 9/60
		+-: 13/60	1+: 1/60	1+: 15/60	5.5: 1/60	1.010: 18/60	+-: 15/60	+-: 27/60		25: 15/60
		1+: 24/60		2+: 4/60	6.0: 1/60	1.015: 10/60	1+: 3/60	1+: 11/60		75: 26/60
		2+: 20/60			6.5: 7/60	1.020: 11/60	2+: 1/60			250: 9/60
		3+: 2/60			7.0: 6/60	1.025: 2/60				500: 1/60
					7.5: 3/60	>1.030: 1/60
					8.0: 23/60
					8.5: 17/60
雌性 Female	-: 60/60	-: 29/60	-: 60/60	NORMAL: 50/60	6.5: 2/60	<1.005: 23/60	-: 55/60	-: 50/60	-: 60/60	-: 41/60
		+-: 17/60		1+: 7/60	7.0: 6/60	1.010: 19/60	+-: 2/60	+-: 8/60		25: 10/60
		1+: 11/60		2+: 2/60	7.5: 3/60	1.015: 15/60	1+: 1/60	1+: 2/60		75: 7/60
		2+: 3/60		3+: 1/60	8.0: 22/60	1.020: 3/60	2+: 1/60			250: 2/10
					8.5: 26/60		3+: 1/60
					9.0: 1/60

药物安全评价用SD大鼠90 d喂养试验的背景数据研究

Study on the 90-day Feeding Experimental Background Data of SD Rats for Drug Safety Evaluation

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Metrics

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脏器 Organ	指标 Index	雄性 Male	雌性 Female
心脏Heart	质量/g	1.685±0.209	1.073±0.140^∗∗∗
	脏体比 (g/100 g)	0.316±0.026	0.364±0.035^∗∗∗
肝脏Liver	质量/g	12.898±2.364	7.411±1.106^∗∗∗
	脏体比 (g/100 g)	2.402±0.221	2.505±0.198^∗∗∗
肺（含支气管）Lungs (with bronchi)	质量/g	1.869±0.247	1.359±0.131^∗∗∗
	脏体比 (g/100 g)	0.352±0.042	0.464±0.054^∗∗∗
脾脏Spleen	质量/g	0.831±0.193	0.528±0.069^∗∗∗
	脏体比 (g/100 g)	0.156±0.033	0.180±0.022^∗∗∗
肾脏Kidney	质量/g	3.247±0.442	1.837±0.298^∗∗∗
	脏体比 (g/100 g)	0.609±0.059	0.622±0.076
脑Brain	质量/g	2.158±0.107	2.010±0.107^∗∗∗
	脏体比 (g/100 g)	0.410±0.054	0.688±0.080^∗∗∗
胸腺Thymus	质量/g	0.405±0.118	0.330±0.101^∗∗∗
	脏体比 (g/100 g)	0.076±0.020	0.111±0.027^∗∗∗
肾上腺Adrenal gland	质量/g	0.064±0.010	0.083±0.086
	脏体比 (g/100 g)	0.012±0.003	0.029±0.036^∗∗∗
睾丸Testis	质量/g	3.591±0.534	/
	脏体比 (g/100 g)	0.678±0.116	/
附睾Epididymis	质量/g	1.483±0.192	/
	脏体比 (g/100 g)	0.280±0.043	/
子宫Uterus	质量/g	/	0.727±0.235
	脏体比 (g/100 g)	/	0.249±0.087
卵巢Ovary	质量/g	/	0.117±0.321
	脏体比 (g/100 g)	/	0.040±0.012

组织器官 Tissue and organ	异常所见 Abnormal finding	病变发生率/% Incidence of lesions/%
组织器官 Tissue and organ	异常所见 Abnormal finding	雄性 Male	雌性 Female
肾脏 Kidney	皮质/髓质/肾盂，单核细胞浸润	45.0	30.0
	嗜碱性肾小管	33.0	10.0
	梗死	1.7	0
	透明管型	10.0	0
	慢性进行性肾病	0	1.7
心脏 Heart	炎性细胞浸润或伴心肌细胞变性/坏死	40.0	5.0
心脏 Heart	心肌病	5.0	3.3
肝脏 Liver	单核细胞浸润	5.0	1.7
	肝细胞空泡变性	18.3	11.7
	小肉芽肿伴或不伴肝细胞坏死	68.3	68.3
脾脏 Spleen	红髓扩张	1.7	3.3
	色素沉着	0	15.0
	髓外造血	0	1.7
	淋巴滤泡减少	1.7	0
胸腺 Thymus	出血	10.0	6.7
胸腺 Thymus	皮质，淋巴细胞/易染体巨噬细胞数目增多	1.7	1.7
肺（含支气管） Lungs (with bronchi)	被膜/间质/血管周围，炎性细胞浸润	6.7	10.0
	泡沫样细胞聚集	16.7	26.7
	肺泡上皮细胞增生	0	3.3
	骨化生	3.3	0
	出血	3.3	0
胰腺 Pancreas	外分泌部，萎缩伴炎性细胞浸润	6.7	8.3
胰腺 Pancreas	胰岛，纤维化	1.7	0
颌下淋巴结 Submandibular lymph nodes	红细胞增多/吞噬作用	1.7	1.7
颌下淋巴结 Submandibular lymph nodes	髓窦，浆细胞增多	1.7	1.7
肠系膜淋巴结 Mesenteric glands	红细胞增多/吞噬作用	0	1.7
垂体 Pituitary gland	囊肿	8.3	0
胃 Stomach	腺腔扩张	3.3	1.7
颈部淋巴结 Cervical lymph node	髓质，浆细胞增多	3.3	0
	红细胞增多/吞噬作用	0	1.7
	出血	5.0	1.7
肾上腺 Adrenal gland	皮质细胞空泡变性	3.3	0
前列腺 Prostate gland	间质，单核细胞浸润	21.7	/
甲状腺 Thyroid gland	滤泡增生	6.7	0
甲状腺 Thyroid gland	间质，单核细胞浸润	0	1.7
睾丸 Testis	单侧或双侧，生精小管萎缩	1.7
附睾 Epididymis	单侧或双侧，精子减少	1.7	/
子宫 Uterus	色素沉着	/	1.7
子宫 Uterus	子宫腔扩张	/	8.3
卵巢 Ovary	/	/	0

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