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Challenges and stepwise fit-for-purpose optimization for bioanalyses of remdesivir metabolites nucleotide monophosphate and triphosphate in mouse tissues using LC-MS/MS.
Hu, Wenjuan; Chang, Lu; Ke, Changqiang; Xie, Yuanchao; Shen, Jingshan; Tan, Bo; Liu, Jia.
  • Hu W; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: wenjuan.hu@simm.ac.cn.
  • Chang L; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: 2893357784@qq.com.
  • Ke C; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: kechangqiang@simm.ac.cn.
  • Xie Y; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: xieyuanchao@simm.ac.cn.
  • Shen J; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: shenjingshan@simm.ac.cn.
  • Tan B; Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: tbot@163.com.
  • Liu J; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jia.liu@simm.ac.cn.
J Pharm Biomed Anal ; 194: 113806, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-1065380
Semantic information from SemMedBD (by NLM)
1. Body tissue PART_OF House mice
Subject
Body tissue
Predicate
PART_OF
Object
House mice
2. Body tissue LOCATION_OF triphosphate
Subject
Body tissue
Predicate
LOCATION_OF
Object
triphosphate
3. Body tissue LOCATION_OF remdesivir
Subject
Body tissue
Predicate
LOCATION_OF
Object
remdesivir
4. COVID-19 drug treatment USES remdesivir
Subject
COVID-19 drug treatment
Predicate
USES
Object
remdesivir
5. Body tissue LOCATION_OF ABCA4|GNA12|URI1
Subject
Body tissue
Predicate
LOCATION_OF
Object
ABCA4|GNA12|URI1
6. Body tissue LOCATION_OF N-Myc Downstream Regulated Protein 1|NDRG1|MORN4
Subject
Body tissue
Predicate
LOCATION_OF
Object
N-Myc Downstream Regulated Protein 1|NDRG1|MORN4
7. ABCA4|GNA12|URI1 INTERACTS_WITH remdesivir
Subject
ABCA4|GNA12|URI1
Predicate
INTERACTS_WITH
Object
remdesivir
8. N-Myc Downstream Regulated Protein 1|NDRG1|MORN4 INTERACTS_WITH remdesivir
Subject
N-Myc Downstream Regulated Protein 1|NDRG1|MORN4
Predicate
INTERACTS_WITH
Object
remdesivir
9. Body tissue PART_OF House mice
Subject
Body tissue
Predicate
PART_OF
Object
House mice
10. Body tissue LOCATION_OF triphosphate
Subject
Body tissue
Predicate
LOCATION_OF
Object
triphosphate
11. Body tissue LOCATION_OF remdesivir
Subject
Body tissue
Predicate
LOCATION_OF
Object
remdesivir
12. COVID-19 drug treatment USES remdesivir
Subject
COVID-19 drug treatment
Predicate
USES
Object
remdesivir
13. Body tissue LOCATION_OF ABCA4|GNA12|URI1
Subject
Body tissue
Predicate
LOCATION_OF
Object
ABCA4|GNA12|URI1
14. Body tissue LOCATION_OF N-Myc Downstream Regulated Protein 1|NDRG1|MORN4
Subject
Body tissue
Predicate
LOCATION_OF
Object
N-Myc Downstream Regulated Protein 1|NDRG1|MORN4
15. ABCA4|GNA12|URI1 INTERACTS_WITH remdesivir
Subject
ABCA4|GNA12|URI1
Predicate
INTERACTS_WITH
Object
remdesivir
16. N-Myc Downstream Regulated Protein 1|NDRG1|MORN4 INTERACTS_WITH remdesivir
Subject
N-Myc Downstream Regulated Protein 1|NDRG1|MORN4
Predicate
INTERACTS_WITH
Object
remdesivir
ABSTRACT
Remdesivir is a prodrug of the nucleotide analogue and used for COVID-19 treatment. However, the bioanalysis of the active metabolites remdesivir nucleotide triphosphate (RTP) and its precursor remdesivir nucleotide monophosphate (RMP) is very challenging. Herein, we established a novel method to separate RTP and RMP on a BioBasic AX column and quantified them by high-performance liquid chromatography-tandem mass spectrometry in positive electrospray ionization mode. Stepwise, we optimized chromatographic retention on an anion exchange column, improved stability in matrix through the addition of 5,5'-dithiobis-(2nitrobenzoic acid) and PhosSTOP EASYpack, and increased recovery by dissociation of tight protein binding with 2 % formic acid aqueous solution. The method allowed lower limit of quantification of 20 nM for RMP and 10 nM for RTP. Method validation demonstrated acceptable accuracy (93.6%-103% for RMP, 94.5%-107% for RTP) and precision (RSD < 11.9 % for RMP, RSD < 11.4 % for RTP), suggesting that it was sensitive and robust for simultaneous quantification of RMP and RTP. The method was successfully applied to analyze RMP and RTP in mouse tissues. In general, the developed method is suitable to monitor RMP and RTP, and provides a useful approach for exploring more detailed effects of remdesivir in treating diseases.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Prodrugs / Adenosine Monophosphate / Alanine / Tandem Mass Spectrometry Limits: Animals / Humans / Male Language: English Journal: J Pharm Biomed Anal Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Prodrugs / Adenosine Monophosphate / Alanine / Tandem Mass Spectrometry Limits: Animals / Humans / Male Language: English Journal: J Pharm Biomed Anal Year: 2021 Document Type: Article