实验动物与比较医学 ›› 2022, Vol. 42 ›› Issue (4): 306-312.DOI: 10.12300/j.issn.1674-5817.2021.163
所属专题: 实验动物伦理与福利专辑
陈佳琦(), 吕龙宝(
)(
), 张飞燕, 李瑞, 李乙江, 李丽红, 张晓迪
收稿日期:
2021-10-25
修回日期:
2021-11-25
出版日期:
2022-08-25
发布日期:
2022-09-01
通讯作者:
吕龙宝(1974—),男,正高级工程师,硕士,研究方向为实验动物的标准化与基础生物学。E-mail:lvlongbao@mail.kiz.ac.cn。ORCID:0000-0002-8437-6333作者简介:
陈佳琦(1987—),女,工程师,硕士,研究方向:实验动物的福利伦理。E-mail:chenjiaqi@mail.kiz.ac.cn
Jiaqi CHEN(), Longbao LÜ(
)(
), Feiyan ZHANG, Rui LI, Yijiang LI, Lihong LI, Xiaodi ZHANG
Received:
2021-10-25
Revised:
2021-11-25
Published:
2022-08-25
Online:
2022-09-01
Contact:
LÜ Longbao (ORCID:0000-0002-8437-6333), E-mail: lvlongbao@mail.kiz.ac.cn摘要:
药物开发中的实验动物福利伦理备受关注,如何善待动物已成为一个重要课题。微量采血法(blood microsampling)克服了常规大容量采血方法操作复杂、对动物的伤害大、对啮齿类动物的数量要求高等诸多缺点,在动物福利、科学性和成本方面均有极大优势,其应用被认为是落实3R原则的重要实践。本文介绍微量采血法的最新研究进展以及在非临床研究中应用的优势和挑战,以期推动这项新技术在药物开发领域内更广泛应用。
中图分类号:
陈佳琦, 吕龙宝, 张飞燕, 李瑞, 李乙江, 李丽红, 张晓迪. 浅谈微量采血法在药物非临床研究中的应用及3R原则的贯彻[J]. 实验动物与比较医学, 2022, 42(4): 306-312.
Jiaqi CHEN, Longbao LÜ, Feiyan ZHANG, Rui LI, Yijiang LI, Lihong LI, Xiaodi ZHANG. Application of Blood Microsampling and Its Implementation of the 3Rs in Non-clinical Studies of Drugs[J]. Laboratory Animal and Comparative Medicine, 2022, 42(4): 306-312.
微量采血法 Blood micro- sampling method | 基质类型 Matrix type | 基质形式 Matrix form | 优点 Advantages | 缺点 Disadvantages |
---|---|---|---|---|
DBS | 全血 | 干燥 | 无需离心,储存和运输方面要求低 | 全血数据与血浆数据转化复杂,HCT效应,需要特殊的提取技术 |
DPS | 血浆 | 干燥 | 储存和运输方面要求低 | 需要特殊的提取技术,可能需要离心 |
VAMS | 全血、血浆、血清 | 干燥 | 储存和运输方面要求低,样品体积准确 | 全血数据与血浆数据转化复杂,血浆、血清制备程序复杂 |
CMS | 全血、血浆、血清 | 液体 | 样品体积准确 | 储存和运输要求高(-20 ℃),血浆、血清制备操作不便 |
表1 非临床研究中几种常见的微量采血法
Table 1 Common approaches for blood microsampling in non-clinical studies
微量采血法 Blood micro- sampling method | 基质类型 Matrix type | 基质形式 Matrix form | 优点 Advantages | 缺点 Disadvantages |
---|---|---|---|---|
DBS | 全血 | 干燥 | 无需离心,储存和运输方面要求低 | 全血数据与血浆数据转化复杂,HCT效应,需要特殊的提取技术 |
DPS | 血浆 | 干燥 | 储存和运输方面要求低 | 需要特殊的提取技术,可能需要离心 |
VAMS | 全血、血浆、血清 | 干燥 | 储存和运输方面要求低,样品体积准确 | 全血数据与血浆数据转化复杂,血浆、血清制备程序复杂 |
CMS | 全血、血浆、血清 | 液体 | 样品体积准确 | 储存和运输要求高(-20 ℃),血浆、血清制备操作不便 |
1 | MACARTHUR CLARK J. The 3Rs in research: a contemporary approach to replacement, reduction and refinement[J]. Br J Nutr, 2018, 120(s1): S1-S7. DOI:10.1017/S0007114517002227 . |
2 | 莫菲. 比较法视野中的实验动物伦理与安全法治模式: 兼谈实验动物法与中国特色动物保护法体系建设的关系[J]. 法学评论, 2021, 39(6):148-158. DOI:10.13415/j.cnki.fxpl.2021.06.013 . |
MO F. Rule of law model of experimental animal ethics and safety in perspective of comparative law[J]. Law Rev, 2021, 39(6):148-158. DOI:10.13415/j.cnki.fxpl.2021.06.013 . | |
3 | CHAPMAN K, CHIVERS S, GLIDDON D, et al. Overcoming the barriers to the uptake of nonclinical microsampling in regulatory safety studies[J]. Drug Discov Today, 2014, 19(5):528-532. DOI:10.1016/j.drudis.2014.01.002 . |
4 | JONSSON O, STEFFEN A C, SUNDQUIST V S, et al. Capillary microsampling and analysis of 4-µl blood, plasma and serum samples to determine human α-synuclein elimination rate in mice[J]. Bioanalysis, 2013, 5(4):449-462. DOI:10.4155/bio.12.337 . |
5 | ICH. Questions and answers to ICH s 3a: note for guidance on toxicokinetics: the assessment of systemic exposure in toxicity studies focus on microsampling [EB/OL]. (2017-11-16). . |
6 | BEAUDETTE P, BATEMAN K P. Discovery stage pharma-cokinetics using dried blood spots[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2004, 809(1):153-158. DOI:10.1016/j.jchromb.2004.06.018 . |
7 | CLARK G T, HAYNES J J, BAYLISS M A J, et al. Utilization of DBS within drug discovery: development of a serial microsampling pharmacokinetic study in mice[J]. Bioanalysis, 2010, 2(8):1477-1488. DOI:10.4155/bio.10.91 . |
8 | BARFIELD M, SPOONER N, LAD R, et al. Application of dried blood spots combined with HPLC-MS/MS for the quantifi-cation of acetaminophen in toxicokinetic studies[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2008, 870(1):32-37. DOI:10.1016/j.jchromb.2008.05.025 . |
9 | COBB Z, DE VRIES R, SPOONER N, et al. In-depth study of homogeneity in DBS using two different techniques: results from the EBF DBS-microsampling consortium[J]. Bioanalysis, 2013, 5(17):2161-2169. DOI:10.4155/bio.13.171 . |
10 | FREY B S, DAMON D E, BADU-TAWIAH A K. Emerging trends in paper spray mass spectrometry: Microsampling, storage, direct analysis, and applications[J]. Mass Spectrom Rev, 2020, 39(4):336-370. DOI:10.1002/mas.21601 . |
11 | CAPIAU S, WILK L S, AALDERS M C G, et al. A novel, nondestructive, dried blood spot-based hematocrit prediction method using noncontact diffuse reflectance spectroscopy[J]. Anal Chem, 2016, 88(12):6538-6546. DOI:10.1021/acs.analchem.6b01321 . |
12 | DAMON D E, YIN M Z, ALLEN D M, et al. Dried blood spheroids for dry-state room temperature stabilization of microliter blood samples[J]. Anal Chem, 2018, 90(15):9353-9358. DOI:10.1021/acs.analchem.8b01962 . |
13 | YOUHNOVSKI N, BERGERON A, FURTADO M, et al. Pre-cut dried blood spot (PCDBS): an alternative to dried blood spot (DBS) technique to overcome hematocrit impact[J]. Rapid Commun Mass Spectrom, 2011, 25(19):2951-2958. DOI:10.1002/rcm.5182 . |
14 | NAKAHARA T, OTANI N, UENO T, et al. Development of a hematocrit-insensitive device to collect accurate volumes of dried blood spots without specialized skills for measuring clozapine and its metabolites as model analytes[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2018, 1087-1088:70-79. DOI:10.1016/j.jchromb.2018.04.019 . |
15 | LENK G, SANDKVIST S, POHANKA A, et al. A disposable sampling device to collect volume-measured DBS directly from a fingerprick onto DBS paper[J]. Bioanalysis, 2015, 7(16):2085-2094. DOI:10.4155/bio.15.134 . |
16 | LI W K, DOHERTY J, FAVARA S, et al. Evaluation of plasma microsampling for dried plasma spots (DPS) in quantitative LC-MS/MS bioanalysis using ritonavir as a model compound[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2015, 991:46-52. DOI:10.1016/j.jchromb.2015.03.026 . |
17 | LI W K, DUGYALA R, DEVINE P J, et al. Application of tail vein serial microsampling for plasma or dried plasma spots in toxicokinetic assessment in rats using acetaminophen as the model compound[J]. Biomed Chromatogr, 2020, 34(10): e4917. DOI:10.1002/bmc.4917 . |
18 | LI Y Y, HENION J, ABBOTT R, et al. The use of a membrane filtration device to form dried plasma spots for the quantitative determination of guanfacine in whole blood[J]. Rapid Commun Mass Spectrom, 2012, 26(10):1208-1212. DOI:10.1002/rcm.6212 . |
19 | STURM R, HENION J, ABBOTT R, et al. Novel membrane devices and their potential utility in blood sample collection prior to analysis of dried plasma spots[J]. Bioanalysis, 2015, 7(16):1987-2002. DOI:10.4155/bio.15.98 . |
20 | RYONA I, HENION J. A book-type dried plasma spot card for automated flow-through elution coupled with online SPE-LC-MS/MS bioanalysis of opioids and stimulants in blood[J]. Anal Chem, 2016, 88(22):11229-11237. DOI:10.1021/acs.analchem.6b03691 . |
21 | HAUSER J, LENK G, ULLAH S, et al. An autonomous microfluidic device for generating volume-defined dried plasma spots[J]. Anal Chem, 2019, 91(11):7125-7130. DOI:10.1021/acs.analchem.9b00204 . |
22 | DENNIFF P, SPOONER N. Volumetric absorptive micro-sampling: a dried sample collection technique for quanti-tative bioanalysis[J]. Anal Chem, 2014, 86(16):8489-8495. DOI:10.1021/ac5022562 . |
23 | SPOONER N, DENNIFF P, MICHIELSEN L, et al. A device for dried blood microsampling in quantitative bioanalysis: overcoming the issues associated blood hematocrit[J]. Bioanalysis, 2015, 7(6):653-659. DOI:10.4155/bio.14.310 . |
24 | THIRY J, EVRARD B, NYS G, et al. Sampling only ten microliters of whole blood for the quantification of poorly soluble drugs: Itraconazole as case study[J]. J Chromatogr A, 2017, 1479:161-168. DOI:10.1016/j.chroma.2016.12.009 . |
25 | NYS G, GALLEZ A, KOK M G M, et al. Whole blood microsampling for the quantitation of estetrol without derivatization by liquid chromatography-tandem mass spectrometry[J]. J Pharm Biomed Anal, 2017, 140:258-265. DOI:10.1016/j.jpba.2017.02.060 . |
26 | KITA K, NORITAKE K, MANO Y. Application of a volumetric absorptive microsampling device to a pharmacokinetic study of tacrolimus in rats: comparison with wet blood and plasma[J]. Eur J Drug Metab Pharmacokinet, 2019, 44(1):91-102. DOI:10.1007/s13318-018-0493-7 . |
27 | DENNIFF P, PARRY S, DOPSON W, et al. Quantitative bioanalysis of paracetamol in rats using volumetric absorptive microsampling (VAMS)[J]. J Pharm Biomed Anal, 2015, 108:61-69. DOI:10.1016/j.jpba.2015.01.052 . |
28 | THIRY J, KOK M G M, COLLARD L, et al. Bioavailability enhancement of itraconazole-based solid dispersions produced by hot melt extrusion in the framework of the Three Rs rule[J]. Eur J Pharm Sci, 2017, 99:1-8. DOI:10.1016/j.ejps.2016.12.001 . |
29 | SPREADBOROUGH M J, DAY J, JACKSON-ADDIE K, et al. Bioanalytical implementation of plasma capillary micro-sampling: small hurdles, large gains[J]. Bioanalysis, 2013, 5(12):1485-1489. DOI:10.4155/bio.13.120 . |
30 | VERHAEGHE T, DILLEN L, STIELTJES H, et al. The application of capillary microsampling in GLP toxicology studies[J]. Bioanalysis, 2017, 9(7):531-540. DOI:10.4155/bio-2016-0297 . |
31 | VERHAEGHE T, DILLEN L, STIELTJES H, et al. Comparison of toxicokinetic parameters of a drug and two metabolites following traditional and capillary microsampling in rat[J]. Bioanalysis, 2019, 11(13):1233-1242. DOI:10.4155/bio-2019-0085 . |
32 | JONSSON O, PALMA VILLAR R, NILSSON L B, et al. Capillary microsampling of 25 µl blood for the determination of toxicokinetic parameters in regulatory studies in animals[J]. Bioanalysis, 2012, 4(6):661-674. DOI:10.4155/bio.12.25 . |
33 | DILLEN L, LOOMANS T, VAN DE PERRE G, et al. Blood microsampling using capillaries for drug-exposure determi-nation in early preclinical studies: a beneficial strategy to reduce blood sample volumes[J]. Bioanalysis, 2014, 6(3):293-306. DOI:10.4155/bio.13.286 . |
34 | WANG B, WANG L N, BATOG A, et al. Investigation on the effect of capillary microsampling on hematologic and toxicokinetic evaluation in regulatory safety studies in mice[J]. AAPS J, 2020, 22(2):55. DOI:10.1208/s12248-020-00438-z . |
35 | RAJE A A, MAHAJAN V, PATHADE V V, et al. Capillary microsampling in mice: effective way to move from sparse sampling to serial sampling in pharmacokinetics profiling[J]. Xenobiotica, 2020, 50(6):663-669. DOI:10.1080/00498254. 2019.1683259 . |
36 | ZHU L, WANG Y, JOYCE A, et al. Fit-for-purpose validation of a ligand binding assay for toxicokinetic study using mouse serial sampling[J]. Pharm Res, 2019, 36(12):169. DOI:10.1007/s11095-019-2699-z . |
37 | BOWEN C L, LICEA-PEREZ H, KARLINSEY M Z, et al. A novel approach to capillary plasma microsampling for quantitative bioanalysis[J]. Bioanalysis, 2013, 5(9):1131-1135. DOI:10.4155/bio.13.58 . |
38 | POWLES-GLOVER N, KIRK S, WILKINSON C, et al. Assessment of toxicological effects of blood microsampling in the vehicle dosed adult rat[J]. Regul Toxicol Pharmacol, 2014, 68(3):325-331. DOI:10.1016/j.yrtph.2014.01.001 . |
39 | BURNETT J E. Dried blood spot sampling: practical consider-ations and recommendation for use with preclinical studies[J]. Bioanalysis, 2011, 3(10):1099-1107. DOI:10.4155/bio.11.68 . |
40 | DIEHL K H, HULL R, MORTON D, et al. A good practice guide to the administration of substances and removal of blood, including routes and volumes[J]. J Appl Toxicol, 2001, 21(1):15-23. DOI:10.1002/jat.727 . |
41 | SPARROW S S, ROBINSON S, BOLAM S, et al. Opportunities to minimise animal use in pharmaceutical regulatory general toxicology: a cross-company review[J]. Regul Toxicol Pharmacol, 2011, 61(2):222-229. DOI:10.1016/j.yrtph.2011.08.001 . |
42 | HOPPER L D. Automated microsampling technologies and enhancements in the 3Rs[J]. ILAR J, 2016, 57(2):166-177. DOI:10.1093/ilar/ilw020 . |
43 | POWLES-GLOVER N, KIRK S, JARDINE L, et al. Assessment of haematological and clinical pathology effects of blood microsampling in suckling and weaned juvenile rats[J]. Regul Toxicol Pharmacol, 2014, 69(3):425-433. DOI:10.1016/j.yrtph. 2014.05.006 . |
44 | NIU X Y, BEEKHUIJZEN M, SCHOONEN W, et al. Effects of capillary microsampling on toxicological endpoints in juvenile rats[J]. Toxicol Sci, 2016, 154(1):69-77. DOI:10.1093/toxsci/kfw146 . |
45 | MITCHARD T, KIRK S, GRANT C, et al. Investigation into the effect of microsampling on mouse fetuses and pregnant mice in the embryofetal development study design[J]. Reprod Toxicol, 2017, 67:140-145. DOI:10.1016/j.reprotox.2016.12.006 . |
46 | PENG S X, ROCKAFELLOW B A, SKEDZIELEWSKI T M, et al. Improved pharmacokinetic and bioavailability support of drug discovery using serial blood sampling in mice[J]. J Pharm Sci, 2009, 98(5):1877-1884. DOI:10.1002/jps.21533 . |
47 | JOYCE A P, WANG M M, LAWRENCE-HENDERSON R, et al. One mouse, one pharmacokinetic profile: quantitative whole blood serial sampling for biotherapeutics[J]. Pharm Res, 2014, 31(7):1823-1833. DOI:10.1007/s11095-013-1286-y . |
48 | KORFMACHER W, FITZGERALD M, LUO Y Y, et al. Capillary microsampling of whole blood for mouse PK studies: an easy route to serial blood sampling[J]. Bioanalysis, 2015, 7(4):449-461. DOI:10.4155/bio.14.275 . |
49 | PATEL N J, WICKREMSINHE E, HUI Y H, et al. Evaluation and optimization of blood micro-sampling methods: serial sampling in a cross-over design from an individual mouse[J]. J Pharm Pharm Sci, 2016, 19(4):496-510. DOI:10.18433/J3NK60 . |
50 | WAN K X, REIMER M T, METCHKAROVA M P, et al. Toxicokinetic evaluation of atrasentan in mice utilizing serial microsampling: validation and sample analysis in GLP study[J]. Bioanalysis, 2012, 4(11):1351-1361. DOI:10.4155/bio.12.91 . |
51 | SPOONER N, ANDERSON K D, SIPLE J, et al. Microsampling: considerations for its use in pharmaceutical drug discovery and development[J]. Bioanalysis, 2019, 11(10):1015-1038. DOI:10.4155/bio-2019-0041 . |
52 | CARON A, LELONG C, BARTELS T, et al. Clinical and anatomic pathology effects of serial blood sampling in rat toxicology studies, using conventional or microsampling methods[J]. Regul Toxicol Pharmacol, 2015, 72(3):429-439. DOI:10.1016/j.yrtph.2015.05.022 . |
53 | HATTORI N, TAKUMI A, SAITO K, et al. Effects of serial cervical or tail blood sampling on toxicity and toxicokinetic evaluation in rats[J]. J Toxicol Sci, 2020, 45(10):599-609. DOI:10.2131/jts.45.599 . |
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