丹蒌片对阿托伐他汀在高脂饲料喂养大鼠体内药动学与药效学的影响

doi:10.12092/j.issn.1009-2501.2026.03.004

中国临床药理学与治疗学 ›› 2026, Vol. 31 ›› Issue (3): 324-336.doi: 10.12092/j.issn.1009-2501.2026.03.004

丹蒌片对阿托伐他汀在高脂饲料喂养大鼠体内药动学与药效学的影响

张珂¹^,²(), 李子婷¹^,², 蒋佛佛¹^,², 赵锋¹, 马银玲¹^,²^,*(), 庞国勋¹^,²^,*()

1. 河北医科大学研究生学院，石家庄 050017，河北
2. 河北省人民医院药学部，石家庄 050051，河北

收稿日期:2025-06-11 修回日期:2025-08-07 出版日期:2026-03-26 发布日期:2026-04-03
通讯作者: 马银玲,庞国勋 E-mail:1789884192@qq.com;paper@hebmu.edu.cn;13503291608@163.com
作者简介:张珂，女，硕士研究生，研究方向：药物代谢动力学。E-mail：1789884192@qq.com
基金资助:
河北省卫生健康委重点医学基金项目资助（20241004）；河北省临床医学优秀人才培养项目资助（ZF2023178）；河北省自然科学基金项目资助（H2020307043）；国家自然科学基金资助（82104288）

Effect of Dan-Lou tablets on the pharmacokinetics and pharmacodynamics of atorvastatin in high-fat diet-fed rats

Ke ZHANG¹^,²(), Ziting LI¹^,², Fofo JIANG¹^,², Feng ZHAO¹, Yinling MA¹^,²^,*(), Guoxun PANG¹^,²^,*()

1. Graduate School of Hebei Medical University, Shijiazhuang 050017, Hebei, China
2. Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, Hebei, China

Received:2025-06-11 Revised:2025-08-07 Online:2026-03-26 Published:2026-04-03
Contact: Yinling MA,Guoxun PANG E-mail:1789884192@qq.com;paper@hebmu.edu.cn;13503291608@163.com

摘要/Abstract

摘要：

目的: 探究在高脂血症中，丹蒌片（Dan-Lou tablets，DLT）调控阿托伐他汀（atorvastatin，ATV）对大鼠体内药动学及药效学的影响，为异常血脂中西药联用提供理论依据。方法: 采用高脂模型，按临床剂量折算单次/多次灌胃DLT，联合ATV干预后，通过UPLC-MS/MS多离子检测法定量检测大鼠血浆中ATV及其活性代谢物浓度，计算药动参数；同时评估高脂模型血脂指标如总胆固醇（total Cholesterol，TC）、甘油三酯（triglyceride，TG）、高密度脂蛋白胆固醇（high-density lipoprotein cholesterol，HDL-C）和低密度脂蛋白胆固醇（low-density lipoprotein cholesterol，LDL-C），并观察肝组织病理形态的变化。结果: 药动学方面，正常组与模型组中，与单独灌服ATV相比，联合用药后ATV的AUC_0-24h分别上升160.63%、50.96%，C_max分别上升27.95%、7.93%。药效学方面，ATV组与联合给药组分别使高脂大鼠的体质量下降12.48%和29.89%，联合给药组的TC、TG和LDL-C均降低，HDL-C升高，差异具有统计学意义（P<0.01）。肝组织切片显示，联合用药组脂滴分布显著减少，改善效果最为明显。结论: 在高脂异常体质中，DLT能影响ATV在大鼠体内的药动学过程，显著增加ATV的体内暴露量。临床联合用药时，应密切监测疗效及药物不良反应，调整给药方案，避免潜在的药物相互作用风险。

关键词: 阿托伐他汀, 丹蒌片, 药动学, 药效学, 液质联用

Abstract:

AIM: To investigate the effects of Dan-Lou tablets (DLT) on the pharmacokinetics and pharmacodynamics of atorvastatin (ATV) in hyperlipidemic rats, and provide theoretical basis for clinical combination therapy of Chinese and Western medicines in dyslipidemia management. METHODS: A high-fat diet-induced hyperlipidemic rat model was established. Following single and multiple oral administrations of DLT at clinical equivalent doses combined with ATV, plasma concentrations of ATV and its active metabolites were quantified using LC-MS/MS with multiple reaction monitoring (MRM) mode. Pharmacokinetic parameters were calculated through non-compartmental analysis. Pharmacodynamic evaluations included serum lipid profiles (TC, TG, HDL-C, LDL-C) and histopathological examination of hepatic tissue. RESULTS: Pharmacokinetic analysis revealed that compared with ATV monotherapy, DLT co-administration increased AUC_0-24h by 160.63% and 50.96% in normal and model groups, respectively, with corresponding C_max elevations of 27.95% and 7.93%. Pharmacodynamically, the combination therapy demonstrated superior effects with 29.89% body weight reduction versus 12.48% in ATV monotherapy group. Significant improvements were observed in lipid profiles: TC, TG and LDL-C decreased by 38.2%, 41.7% and 52.4% respectively, while HDL-C increased by 28.6% (all P<0.01). Hepatic histopathology showed remarkable reduction of lipid droplet accumulation in combination group compared to monotherapy. CONCLUSION: DLT significantly enhances systemic exposure of ATV in hyperlipidemic conditions by altering its pharmacokinetic profile. These findings suggest that when combining DLT with ATV in clinical practice, therapeutic efficacy and potential adverse reactions should be closely monitored, with particular attention to adjusting ATV dosing regimens to mitigate potential drug interaction risks.

Key words: atorvastatin, Dan-Lou tablets, pharmacokinetics, pharmacodynamics, UPLC-MS/MS

中图分类号:

R965.2

张珂, 李子婷, 蒋佛佛, 赵锋, 马银玲, 庞国勋. 丹蒌片对阿托伐他汀在高脂饲料喂养大鼠体内药动学与药效学的影响[J]. 中国临床药理学与治疗学, 2026, 31(3): 324-336.

Ke ZHANG, Ziting LI, Fofo JIANG, Feng ZHAO, Yinling MA, Guoxun PANG. Effect of Dan-Lou tablets on the pharmacokinetics and pharmacodynamics of atorvastatin in high-fat diet-fed rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(3): 324-336.

图/表 17

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Compound	ATV	o-ATV	p-ATV	CMZ (IS)
Quantitative ion transition (m/z)	559.3→440.6	575.3→440.3	575.3→440.3	237.2→194.2
DP, V	130	91	91	110
CE, eV	30	33	33	13

Compound	ATV	o-ATV	p-ATV	CMZ (IS)
Quantitative ion transition (m/z)	559.3→440.6	575.3→440.3	575.3→440.3	237.2→194.2
DP, V	130	91	91	110
CE, eV	30	33	33	13

Group	Body weight (g)	TC (mmol/L)	TG (mmol/L)	HDL-C (mmol/L)	LDL-C (mmol/L)
Normal diet group	185.33±3.96	1.39±0.21	0.13±0.03	2.66±0.11	0.46±0.03
High-fat diet group	373.33±34.58^c	3.36±0.38^c	0.93±0.38^c	0.74±0.11^c	1.03±0.02^c

Group	Body weight (g)	TC (mmol/L)	TG (mmol/L)	HDL-C (mmol/L)	LDL-C (mmol/L)
Normal diet group	185.33±3.96	1.39±0.21	0.13±0.03	2.66±0.11	0.46±0.03
High-fat diet group	373.33±34.58^c	3.36±0.38^c	0.93±0.38^c	0.74±0.11^c	1.03±0.02^c

Compound	Concentration (ng/mL)	Intra-day			Inter-day
Compound	Concentration (ng/mL)	Determined concentrations (ng/mL)	Accuracy (%)	RSD (%)	Determined concentrations (ng/mL)	Accuracy (%)	RSD (%)
ATV	0.1	0.11±0.005	9.00	4.93	0.11±0.002	10.20	1.54
	0.5	0.46±0.03	?7.49	6.15	0.47±0.009	?6.16	2.00
	100	97.01±3.16	?2.99	3.26	98.24±1.73	?1.76	1.76
	250	249.71±4.82	?0.11	1.93	251.43±2.42	0.57	0.96
o-ATV	0.1	0.11±0.003	7.58	3.14	0.11±0.004	7.70	3.80
	0.5	0.46±0.009	?7.19	1.93	0.46±0.004	?7.74	0.84
	10	9.48±0.34	?10.50	7.52	10.54±0.09	?4.62	1.97
	24	24.55±0.84	2.27	3.41	24.63±0.12	2.61	0.47
p-ATV	0.1	0.11±0.006	12.08	5.23	0.11±0.008	12.72	7.07
	0.5	0.52±0.02	3.00	3.59	0.51±0.003	2.54	0.61
	10	10.42±0.13	4.22	1.20	10.42±1.39	4.19	0.13
	24	22.13±0.66	?7.80	3.00	22.00±0.11	?8.34	0.52

丹蒌片对阿托伐他汀在高脂饲料喂养大鼠体内药动学与药效学的影响

Effect of Dan-Lou tablets on the pharmacokinetics and pharmacodynamics of atorvastatin in high-fat diet-fed rats

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Compound	Concentration (ng/mL)	Extraction Recovery%	RSD%	Matrix effect%	RSD%
ATV	0.5	91.24	3.98	111.29	10.17
	150	105.92	8.35	113.99	11.92
	300	103.65	11.38	109.83	12.36
o-ATV	0.5	97.44	7.21	97.32	5.84
	10	92.05	7.70	102.17	11.02
	24	104.63	11.64	95.12	12.89
p-ATV	0.5	100.14	9.12	101.22	10.98
	10	103.35	9.86	96.32	5.94
	24	97.15	10.27	102.20	8.58

Compound	Concentration (ng/mL)	Room temperature for 2 h		8 h at 4 ℃		Three freezes-thraws (?80 ℃)
Compound	Concentration (ng/mL)	Measured concentration (ng/mL)	RSD%	Measured concentration (ng/mL)	RSD%	Measured concentration (ng/mL)	RSD%
ATV	0.5	0.56±0.02	3.04	0.54±0.03	5.84	0.53±0.03	5.97
	100	105.60±3.21	3.04	105.40±3.21	3.04	103.80±2.59	2.49
	250	245.60± 9.58	3.90	247±5.52	2.24	245.80±8.81	3.59
o-ATV	0.5	0.46±0.01	1.17	0.46±0.01	1.66	0.46±0.004	0.87
	10	9.34±0.35	3.70	9.64±0.21	2.19	9.64±0.19	1.96
	24	24.17±0.86	3.57	24.18±0.81	3.36	24.24±1.02	4.21
p-ATV	0.5	0.53±0.02	4.71	0.50±0.003	0.51	0.53±0.02	3.70
	10	10.43±0.28	2.68	10.32±0.19	1.82	10.43±0.13	1.23
	24	22.86±0.61	2.65	23.12±0.80	3.48	21.73±0.22	0.99

Pharmacokinetic parameters	Normal group			High-fat diet group
Pharmacokinetic parameters	ATV	DLT+ATV	DLT (7days)+ATV	ATV	DLT+ATV	DLT (7days)+ATV
AUC_0-24h (μg·L^?1h^?1)	127.58±43.22	331.06±222.726^c	108.73±23.30	148.92±43.53	224.81±123.74	308.87±18.87^b
AUC_0-∞ (μg·L^?1h^?1)	129.75±42.85	465.86±455.58^c	131.27±35.42	165.25±43.29	487.11±600.05	856.88±367.62^b
t_1/2z(h)	3.22±1.25	14.35±14.01^c	9.93±7.81^c	10.62±5.18	38.38±44.13^b	40.62±22.54^b
T_max(h)	0.23±0.18	0.22±0.17	0.13±0.05^c	0.25±0.29	0.62±0.82	0.12±0.08
V_z/F(L/kg)	138.65±62.30	177.40±111.67	358.57±212.41^c	357.36±198.04	447.57±483.68	227.31±64.91
CL_z/F (L·h^?1kg^?1)	30.13±9.16	11.92±5.83^c	29.24±8.49	23.14±6.49	14.07±7.32	5.28±3.36^b
C_max(μg/L)	94.84±89.49	187.45±124.56^c	70.03±37.36^b	89.41±41.43	96.50±56.34	143.95±79.01

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Pharmacokinetic parameters	Normal group			High-fat diet group
Pharmacokinetic parameters	ATV	DLT+ATV	DLT (7days)+ATV	ATV	DLT+ATV	DLT (7days)+ATV
AUC_0-24h (μg·L^?1h^?1)	39.86±11.09	133.02±18.86^c	34.16±4.44	42.98±10.38	52.86±16.54	33.05±13.30^b
AUC_0-∞ (μg·L^?1h^?1)	40.25±11.84	134.95±47.93^c	34.24±4.38	54.36±33.87	53.01±16.45	36.91±16.95^b
t_1/2z(h)	2.72±1.08	4.36±1.73^c	2.56±0.71	9.70±12.80	2.75±0.68	7.31±4.02^b
T_max(h)	2.10±2.24	0.28±0.14^c	1.35±0.60^c	1.85±1.39	1.60±0.55	1.95±2.35
C_max(μg/L)	7.53±2.00	52.76±14.61^c	5.90±1.81^b	7.91±3.75	9.95±5.92	6.41±5.42

Pharmacokinetic parameters	Normal group			High-fat diet group
Pharmacokinetic parameters	ATV	DLT+ATV	DLT (7days)+ATV	ATV	DLT+ATV	DLT (7days)+ATV
AUC_0-24h (μg·L^?1h^?1)	39.86±11.09	133.02±18.86^c	34.16±4.44	42.98±10.38	52.86±16.54	33.05±13.30^b
AUC_0-∞ (μg·L^?1h^?1)	40.25±11.84	134.95±47.93^c	34.24±4.38	54.36±33.87	53.01±16.45	36.91±16.95^b
t_1/2z(h)	2.72±1.08	4.36±1.73^c	2.56±0.71	9.70±12.80	2.75±0.68	7.31±4.02^b
T_max(h)	2.10±2.24	0.28±0.14^c	1.35±0.60^c	1.85±1.39	1.60±0.55	1.95±2.35
C_max(μg/L)	7.53±2.00	52.76±14.61^c	5.90±1.81^b	7.91±3.75	9.95±5.92	6.41±5.42

Pharmacokinetic parameters	Normal group			High-fat diet group
Pharmacokinetic parameters	ATV	DLT+ATV	DLT (7days)+ATV	ATV	DLT+ATV	DLT (7days)+ATV
AUC_0-24h (μg·L^?1h^?1)	26.16±17.51	23.18±7.42	10.75±1.10^c	21.00±15.08	17.11±3.22	16.24±1.77
AUC_0-∞ (μg·L^?1h^?1)	28.54±15.79	26.35±9.08	15.51±4.54^c	110.81±178.04	23.12±1.99	23.46±6.13
t_1/2z(h)	8.64±10.31	9.10±4.86	13.33±7.23^b	152.50±287.83	13.71±7.21	13.23±9.71
T_max(h)	3.10±2.70	0.23±0.07^c	3.60±1.67	2.25±1.70	2.80±1.10	4.40±1.67
C_max(μg/L)	12.83±15.70	7.89±5.70^b	0.85±0.12^c	8.10±15.28	1.72±0.62	1.51±0.67

Pharmacokinetic parameters	Normal group			High-fat diet group
Pharmacokinetic parameters	ATV	DLT+ATV	DLT (7days)+ATV	ATV	DLT+ATV	DLT (7days)+ATV
AUC_0-24h (μg·L^?1h^?1)	26.16±17.51	23.18±7.42	10.75±1.10^c	21.00±15.08	17.11±3.22	16.24±1.77
AUC_0-∞ (μg·L^?1h^?1)	28.54±15.79	26.35±9.08	15.51±4.54^c	110.81±178.04	23.12±1.99	23.46±6.13
t_1/2z(h)	8.64±10.31	9.10±4.86	13.33±7.23^b	152.50±287.83	13.71±7.21	13.23±9.71
T_max(h)	3.10±2.70	0.23±0.07^c	3.60±1.67	2.25±1.70	2.80±1.10	4.40±1.67
C_max(μg/L)	12.83±15.70	7.89±5.70^b	0.85±0.12^c	8.10±15.28	1.72±0.62	1.51±0.67