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Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease

Thiopurine therapy of inflammatory bowel disease (IBD) is guided by the relative blood concentrations 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). However, their action is altered by in vivo phosphorylation, and this is not normally measured in clinical studies. Hence, we tr...

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Main Authors: Lim, Sheng Zhang, Raja Affendi Raja Ali,, Suzana Makpol,, Chua, Eng Wee
Format: Article
Language:English
Published: Penerbit Universiti Kebangsaan Malaysia 2022
Online Access:http://journalarticle.ukm.my/19757/1/20.pdf
http://journalarticle.ukm.my/19757/
https://www.ukm.my/jsm/malay_journals/jilid51bil6_2022/KandunganJilid51Bil6_2022.html
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spelling my-ukm.journal.197572022-09-19T07:04:27Z http://journalarticle.ukm.my/19757/ Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease Lim, Sheng Zhang Raja Affendi Raja Ali, Suzana Makpol, Chua, Eng Wee Thiopurine therapy of inflammatory bowel disease (IBD) is guided by the relative blood concentrations 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). However, their action is altered by in vivo phosphorylation, and this is not normally measured in clinical studies. Hence, we trialled a novel method for profiling phosphorylated thiopurine metabolites and revisited the association between thiopurine metabolites and IBD treatment outcomes. We first optimised and validated a published high-performance liquid chromatography (HPLC) method for measuring the blood levels of thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), thioguanosine triphosphate (TGTP), and methylthioinosine monophosphate (MeTIMP). Then, we assembled a small cohort of IBD patients (n = 20), who had been treated with azathioprine for at least three months, and obtained blood samples for analysis of the metabolites. The patients received treatments at the Universiti Kebangsaan Malaysia Specialist Centre between March 2018 and April 2019. They were classified as responders (n = 12) or non-responders (n = 6) to azathioprine based on their disease activity scores (CDAI or Mayo score). The HPLC method was precise with intraday and interday variation < 15% for all the tested metabolites, and the relative accuracy ranged from 40.2 to 114.0%. We noted that the responders had higher median 6-TGN but lower median TGTP levels than the non-responders. However, the differences were not statistically significant (Wilcoxon rank-sum tests; 6-TGN, p = 0.925; TGTP, p = 0.189). The higher median 6-TGN level detected in the responders is in keeping with the findings of prior studies, suggesting that HPLC analysis of phosphorylated thiopurine metabolites is both technically feasible and clinically useful. Penerbit Universiti Kebangsaan Malaysia 2022-06 Article PeerReviewed application/pdf en http://journalarticle.ukm.my/19757/1/20.pdf Lim, Sheng Zhang and Raja Affendi Raja Ali, and Suzana Makpol, and Chua, Eng Wee (2022) Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease. Sains Malaysiana, 51 (6). pp. 1847-1859. ISSN 0126-6039 https://www.ukm.my/jsm/malay_journals/jilid51bil6_2022/KandunganJilid51Bil6_2022.html
institution Universiti Kebangsaan Malaysia
building Tun Sri Lanang Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Kebangsaan Malaysia
content_source UKM Journal Article Repository
url_provider http://journalarticle.ukm.my/
language English
description Thiopurine therapy of inflammatory bowel disease (IBD) is guided by the relative blood concentrations 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). However, their action is altered by in vivo phosphorylation, and this is not normally measured in clinical studies. Hence, we trialled a novel method for profiling phosphorylated thiopurine metabolites and revisited the association between thiopurine metabolites and IBD treatment outcomes. We first optimised and validated a published high-performance liquid chromatography (HPLC) method for measuring the blood levels of thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), thioguanosine triphosphate (TGTP), and methylthioinosine monophosphate (MeTIMP). Then, we assembled a small cohort of IBD patients (n = 20), who had been treated with azathioprine for at least three months, and obtained blood samples for analysis of the metabolites. The patients received treatments at the Universiti Kebangsaan Malaysia Specialist Centre between March 2018 and April 2019. They were classified as responders (n = 12) or non-responders (n = 6) to azathioprine based on their disease activity scores (CDAI or Mayo score). The HPLC method was precise with intraday and interday variation < 15% for all the tested metabolites, and the relative accuracy ranged from 40.2 to 114.0%. We noted that the responders had higher median 6-TGN but lower median TGTP levels than the non-responders. However, the differences were not statistically significant (Wilcoxon rank-sum tests; 6-TGN, p = 0.925; TGTP, p = 0.189). The higher median 6-TGN level detected in the responders is in keeping with the findings of prior studies, suggesting that HPLC analysis of phosphorylated thiopurine metabolites is both technically feasible and clinically useful.
format Article
author Lim, Sheng Zhang
Raja Affendi Raja Ali,
Suzana Makpol,
Chua, Eng Wee
spellingShingle Lim, Sheng Zhang
Raja Affendi Raja Ali,
Suzana Makpol,
Chua, Eng Wee
Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease
author_facet Lim, Sheng Zhang
Raja Affendi Raja Ali,
Suzana Makpol,
Chua, Eng Wee
author_sort Lim, Sheng Zhang
title Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease
title_short Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease
title_full Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease
title_fullStr Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease
title_full_unstemmed Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease
title_sort therapeutic monitoring of thiopurine metabolites : validation of an hplc method and preliminary findings from a small cohort of malaysian patients with inflammatory bowel disease
publisher Penerbit Universiti Kebangsaan Malaysia
publishDate 2022
url http://journalarticle.ukm.my/19757/1/20.pdf
http://journalarticle.ukm.my/19757/
https://www.ukm.my/jsm/malay_journals/jilid51bil6_2022/KandunganJilid51Bil6_2022.html
_version_ 1744649876144128000
score 13.211869

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