替加环素血药浓度监测与不良反应的关联性分析

doi:10.12092/j.issn.1009-2501.2026.09.010

摘要/Abstract

摘要：

目的: 建立人血浆中替加环素的高效液相色谱-串联质谱（HPLC-MS/MS）测定方法，用于研究患者体内的药代动力学特征，并探讨其血药浓度与药物诱导性肝损伤及凝血功能障碍的相关性。方法: 采用蛋白沉淀法处理血浆，以Eclipse Plus C₁₈柱分离，0.1%甲酸水-甲醇梯度洗脱，利血平为内标，流速0.3 mL/min，正离子模式检测并考察方法各项性能。随后，收集2024年6月至2025年6月期间使用替加环素患者的临床资料与血浆样本（n=72）。根据是否发生不良反应（ADR）分组，比较两组血药浓度差异，采用受试者工作特征曲线（ROC）分析确定ADR发生的血药浓度折点，并计算敏感度、特异度及曲线下面积（AUC）。结果: 所建方法线性范围为50～5 000 ng/mL，精密度、准确度及稳定性值均小于10%，满足临床检测要求。通过ROC曲线得到替加环素导致肝损伤的折点为515.34 ng/mL，致凝血功能障碍的折点为243.59 ng/mL。结论: 成功建立人血浆中替加环素的HPLC-MS/MS方法，替加环素的血药浓度与导致肝损伤及凝血功能障碍有关，建议临床上应联合血药浓度与肝功能、凝血指标监测以守护用药安全。

关键词: 替加环素, 血药浓度监测, HPLC-MS/MS, 药代动力学, 肝损伤, 凝血功能障碍

Abstract:

AIM: To establish a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of tigecycline in human plasma, which was used to study the pharmacokinetic profile in patients and to investigate the correlation between its blood concentration and drug-induced hepatic injury and coagulation dysfunction. METHODS: Plasma was processed by protein precipitation, separated on an Eclipse Plus C₁₈ column, eluted by a 0.1% formic acid water-methanol gradient, with Reserpine as an internal standard, at a flow rate of 0.3 mL/min and detected in the positive ion mode and examined the method properties. Subsequently, clinical data with plasma samples were collected from patients using tigecycline between June 2024 and June 2025 (n=72). The groups were grouped according to whether or not an adverse reaction (ADR) occurred, the differences in blood concentrations between the two groups were compared, and the blood concentration breakpoints at which ADRs occurred were determined using subject's work characterization curve (ROC) analysis, and the sensitivity, specificity, and area under the curve (AUC) were calculated. RESULTS: The linear range of the proposed method was 50-5000 ng/mL, and the precision, accuracy and stability values were less than 10%, which met the requirements of clinical testing. The ROC curve showed that the fold point of tigecycline causing liver injury was 515.34 ng/mL, and that of coagulation dysfunction was 243.59 ng/mL. CONCLUSION: The HPLC-MS/MS of tigecycline in human plasma was successfully established, and the tigecycline blood concentration is related to the cause of liver injury and coagulation dysfunction. It is recommended that blood concentration monitoring combined with liver function and coagulation indicators should be applied clinically to ensure medication safety.

Key words: tigecycline, therapeutic drug monitoring, HPLC-MS/MS, pharmacokinetics, liver injury, coagulation-disorders

中图分类号:

R969.3

吴诗雅, 刘晓丹, 胡妍, 林琦. 替加环素血药浓度监测与不良反应的关联性分析[J]. 中国临床药理学与治疗学, 2026, 31(9): 1238-1248.

Shiya WU, Xiaodan LIU, Yan HU, Qi LIN. Correlation analysis between tigecycline therapeutic concentration monitoring and adverse reactions[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(9): 1238-1248.

图/表 11

参考文献 33

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Compound	Ion pair type	Precursor Ion (m/z)	Product Ion (m/z)	Exit voltage (V)	Collision energy (eV)
TGC	Quantitative ion-pairing	586.3	513.1	180	30
TGC	Qualitative ion pair	586.3	569.2	180	20
Reserpine	Quantitative ion-pairing	609.2	195.0	110	40
Reserpine	Qualitative ion pair	609.2	173.4	110	50

Compound	Ion pair type	Precursor Ion (m/z)	Product Ion (m/z)	Exit voltage (V)	Collision energy (eV)
TGC	Quantitative ion-pairing	586.3	513.1	180	30
TGC	Qualitative ion pair	586.3	569.2	180	20
Reserpine	Quantitative ion-pairing	609.2	195.0	110	40
Reserpine	Qualitative ion pair	609.2	173.4	110	50

Nominal Concentration (ng/mL)		Run 1	Run 2	Run 3
Nominal Concentration (ng/mL)		?
50		0.0104897	0.0112690	0.0115818
100		0.0206517	0.0211542	0.0219776
200		0.0435247	0.0422220	0.0447260
500		0.0892320	0.0952995	0.0871738
1000		0.1692829	0.1533830	0.1636522
2000		0.3422944	0.3192495	0.3483906
3000		0.5121539	0.5044906	0.4950652
5000		0.8779048	0.8635990	0.8622892
Parameter	a	0.0001736	0.0001703	0.0001700
	b	0.001016	?0.0009	0.002409
	r	0.9995	0.9982	0.9991

Nominal Concentration (ng/mL)		Run 1	Run 2	Run 3
Nominal Concentration (ng/mL)		?
50		0.0104897	0.0112690	0.0115818
100		0.0206517	0.0211542	0.0219776
200		0.0435247	0.0422220	0.0447260
500		0.0892320	0.0952995	0.0871738
1000		0.1692829	0.1533830	0.1636522
2000		0.3422944	0.3192495	0.3483906
3000		0.5121539	0.5044906	0.4950652
5000		0.8779048	0.8635990	0.8622892
Parameter	a	0.0001736	0.0001703	0.0001700
	b	0.001016	?0.0009	0.002409
	r	0.9995	0.9982	0.9991

Batch	LLOQ (50 ng/mL)	Accuracy	LQC1 (150 ng/mL)	Accuracy	LQC2 (750 ng/mL)	Accuracy	MQC (3000 ng/mL)	Accuracy	HQC (4500 ng/mL)	Accuracy
First batch	49.42	98.84	152.72	101.81	757.74	101.03	3070.49	102.35	4491.45	99.81
	51.13	102.26	150.63	100.42	756.50	100.87	3015.87	100.53	4508.53	100.19
	48.73	97.46	156.20	104.13	747.38	99.65	3064.82	102.16	4509.69	100.22
	49.58	99.16	151.84	101.23	757.59	101.01	3038.98	101.30	4517.66	100.39
	52.13	104.26	148.94	99.29	756.22	100.83	3073.57	102.45	4588.20	101.96
Mean	50.20		152.07		755.09		3052.75		4523.11
SD	1.39		2.71		4.36		24.72		37.62
Intra-batch CV%	2.77		1.78		0.58		0.81		0.83
Intra-batch Accuracy (%)	0.40		1.38		3.39		1.76		0.51
Second batch	51.70	103.40	152.91	101.94	748.01	99.73	3081.22	102.71	4422.70	98.28
	49.97	99.94	149.16	99.44	747.89	99.72	3059.91	102.00	4518.38	100.41
	52.32	104.64	146.54	97.69	759.12	101.22	3016.10	100.54	4468.88	99.31
	49.12	98.24	151.29	100.86	755.76	100.77	2946.45	98.22	4572.92	101.62
	52.36	104.72	149.57	99.71	750.76	100.10	2942.75	98.09	4526.11	100.58
Mean	51.09		149.89		752.31		3009.29		4501.80
SD	1.47		2.39		4.97		63.56		57.59
Intra-batch CV%	2.88		1.60		0.66		2.11		1.28
Intra-batch Accuracy (%)	2.19		?0.07		1.54		0.31		0.04
Third batch	48.35	96.70	156.43	104.29	758.76	101.17	3097.68	103.26	4591.62	102.04
	53.94	107.88	156.02	104.01	745.76	99.43	3085.69	102.86	4581.90	101.82
	54.09	108.18	148.81	99.21	745.76	99.43	2900.04	96.67	4486.38	99.70
	53.09	106.18	148.59	99.06	757.76	101.03	2972.74	99.09	4527.42	100.61
	53.04	106.08	153.26	102.17	754.76	100.63	3002.13	100.07	4594.60	102.10
Mean	52.50		152.62		752.56		3011.66		4556.38
SD	2.37		3.78		6.38		82.07		47.68
Intra-batch CV%	4.51		2.48		0.85		2.73		1.05
Intra-batch Accuracy (%)	5.00		1.75		1.71		0.39		1.25
Mean Calculated Concentration	51.26		151.53		753.32		3024.56		4527.10
Inter-batch CV%	3.77		2.01		0.67		2.01		1.11
Intra-batch accuracy (%)	2.53		1.02		2.21		0.82		0.60