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Correlation of thiopurine methyltransferase activity and 6-thioguanine nucleotide concentration in Han Chinese patients treated with azathioprine 25 to 100 mg: A 1-year, single-center, prospective study. | LitMetric

Background: Of the enzymes involved in the metabolism of azathioprine, thiopurine methyltransferase (TPMT) is the one characterized by genetic polymorphisms and ethnic variations. There have been several studies of the ethnic variations in phenotype and genotype of TPMT, although few have assessed the possible correlation between TPMT activity and 6-thioguanine nucleotide (6-TGN) concentrations.

Objective: The aim of this study was to examine the relationship between TPMT activity and the steady-state concentration (Css) of 6-TGN, the primary active metabolite of azathioprine, in red blood cells (RBCs) in Han Chinese patients treated with azathioprine.

Methods: Han Chinese patients aged 18 to 60 years with immunosuppression and normal hepatic and renal function who had been receiving a stable dose (25-100 mg/d) of oral azathioprine as a part of their regular anti-immunosuppression regimen for at least 10 days were recruited for this 1-year, single-center, prospective study. Azathioprine was administered PO QD in the morning, in combination with a stable regimen of other immunosuppressive drugs, for 1 year. At 1 year, blood samples were drawn just before the ingestion of azathioprine. TPMT activity and 6-TGN Css in RBCs were determined in our laboratory using high-performance liquid chromatography. Adverse drug events were monitored by a patient questionnaire and laboratory testing. Out of the initial cohort, several patients were concurrently enrolled in a subanalysis in which the effect of TPMT polymorphism on the pharmacokinetic properties of 6-mercaptopurine, the intermediate metabolite of azathioprine, was examined.

Results: Nineteen patients (14 women, 5 men; mean [SD] age, 41 [9.6] years [range, 22-59 years]; mean [SD] weight, 62 [12] kg) were included in the study; 7 were included in the subanalysis. A significant negative correlation was found between TPMT activity and 6-TGN Css in RBCs (r = -0.712; P = 0.001); when the outlier data were removed, no significant correlation was found. Mean (SD) TPMT activity was 12.95 (3.07) nmol/h · mL(-1) RBCs and the interindividual CV was 23.68%. Mean (SD) 6-TGN CSS was 42.95 (41.98) ng/8 × 108 RBCs and the interindividual CV was 97.74% (N = 19), while the intraindividual CV of 6-TGNs within 8 hours after azathioprine ingestion was between 4.23% and 7.37% (n = 7). No significant correlation was found between 6-TGN Css in RBCs and the dose of azathioprine used. One patient's treatment was discontinued because her white blood cell count decreased to < 4 × 109 cells/L, indicating myelotoxicity; the t/12 of 6-TGNs in this patient was 5.85 days. Treatment was well tolerated by all other patients.

Conclusion: In this small study, a significant negative correlation was found between TPMT activity and 6-TGN concentration in the RBCs of these Han Chinese patients. However, the correlation was not significant when data from 1 patient with low TPMT activity were excluded.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966017PMC
http://dx.doi.org/10.1016/j.curtheres.2006.07.002DOI Listing

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