Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease
Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease
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DOI：
10.1080/00365520150218084
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发表时间：
2001-01-01
影响因子：
1.9
通讯作者：
Louis, E
中科院分区：
文献类型：
--
作者：
Belaiche, J;Desager, JP;Louis, E
背景：6-巯基嘌呤（6-MP）及其前体药物硫唑嘌呤（AZA）已被证实在治疗克罗恩病（CD）中有效。AZA/6-MP的免疫抑制特性通过6-MP的细胞内代谢成其活性代谢物6-硫代鸟嘌呤核苷酸（6-TGN）和6-甲巯基嘌呤（6-MMP）来介导。初步研究表明，6 TGN的红细胞浓度（RBC 6 TGN）是一个潜在的治疗指南。本研究的目的是评价长期接受AZA/6-MP治疗的成人CD患者的RBC 6 TGN浓度，并将其与治疗反应和血液学参数相关联。方法：对28例CD患者进行前瞻性研究，患者接受AZA/6-MP治疗至少3个月。患者分为三个主要组：第1组（n = 19），对应于静止期CD接受AZA（剂量：2.05 +/- 0.4 mg/kg/天，平均28.6 +/- 25个月）或6-MP（剂量：1.4 +/- 01 mg/kg/天，平均7.5 +/- 3.5个月）单独给药;第2组（n = 6），对应于AZA治疗的静止期CD（剂量：2.14 +/- 0.5 mg/kg/天，平均29.5 +/- 22个月）;和第3组（n = 3），对应于AZA（剂量：1.94 +/- 0.6 mg/kg/天，平均31.3 +/- 35个月）作为唯一治疗的活动性CD。还通过合并组I和2形成由临床缓解定义的较大患者组（n = 25）和组2和3形成较大患者组（n=9）（单独使用AZA/6-MP的非完全应答者）来进行评估。在入选时和6个月时（n = 17）评价克罗恩病指数活动（CDAI）、全血细胞计数和分类白色细胞计数的血液样本以及RBC 6 TGN和6-MMP浓度的测量。采用高效液相色谱法（HPLC）对肝素化血液进行RBC 6 TGN测定。结果：三组患者的基线特征相似。三组患者在免疫抑制治疗的剂量和持续时间方面无显著差异。根据测试的各种参数，组间无显著差异。特别是，三组患者入选时的中位RBC 6 TGN浓度相似（分别为166（105-688）、183（90-261）和160（52-194）pmol/8 x 10（8）RBC）。除3例患者外，大多数患者的6-MMP代谢产物水平均不可检测。合并组之间也没有差异。此外，RBC 6 TGN浓度与除平均红细胞体积外的各种生物学参数之间无显著相关性。6个月时，第1组所有患者均保持缓解，中位RBC 6 TGN浓度保持稳定。未观察到副作用。结论：与初步研究相反，AZA/6-MP治疗缓解或未缓解患者和应答或未应答患者的RBC 6 TGN水平以及血液学参数存在广泛重叠。这表明，除了这些药物代谢的变异性之外，还存在复杂的作用机制。然而，除了使用RBC 6 TGN测定来确认对治疗的依从性之外，该剂量在无应答患者中可能是有用的，允许在没有白细胞减少症的情况下安全地增加AZA/6-MP的剂量。
Background: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) have proven efficacy in the treatment of Crohn disease (CD). The immunosuppressive properties of AZA/6-MP are mediated by the intracellular metabolism of 6-MP into its active metabolites, 6-thioguanine nucleotides (6TGN) and 6-methylmercaptopurine (6-MMP). Preliminary studies have suggested that the red blood cell concentration of 6TGN (RBC 6TGN) is a potential guide to therapy. The aims of the study were to evaluate the RBC 6TGN concentrations in adult patients with CD under long-term AZA/6-MP therapy and to correlate it with response to treatment and haematological parameters. Methods: Twenty-eight CD patients treated for at least 3 months with AZA/6-MP were prospectively studied. Patients were separated into three main groups: group 1 (n = 19), corresponding to quiescent CD receiving AZA (dose: 2.05 +/- 0.4 mg/kg/day for a mean of 28.6 +/- 25 months) or 6-MP (dose: 1.4 +/- 01 mg/kg/day for a mean of 7.5 +/- 3.5 months) alone; group 2 (n = 6), corresponding to quiescent CD treated by AZA (dose: 2.14 +/- 0.5 mg/kg/day for a mean of 29.5 +/- 22 months) with oral steroids; and group 3 (n = 3), corresponding to active CD on AZA (dose: 1.94 +/- 0.6 mg/kg/day for a mean of 31.3 +/- 35 months) as the only treatment. An assessment was also made by merging groups I and 2 forming a larger group of patients (n = 25) defined by clinical remission and groups 2 and 3 forming a larger group of patients (n=9), non-complete responders with AZA/6-MP alone. Crohn disease index activity (CDAI), blood samples for full blood count and differential white cell count and measurement of RBC 6TGN and 6-MMP concentrations were evaluated at inclusion and at 6 months (n = 17). RBC 6TGN were measured using high performance liquid chromatography (HPLC) on heparinized blood. Results: The baseline characteristics of the three groups of patients were similar. There was no significant difference among the three groups of patients regarding the dose and the duration of immunosuppressive treatment. There was no significant difference between groups according to various parameters tested. Particularly, the median RBC 6TGN concentration at inclusion was similar in the three groups of patients (166 (105-688), 183 (90-261) and 160 (52-194) pmol/8 x 10(8) RBC, respectively). The majority of patients had no detectable level of 6-MMP metabolite, except for 3 patients. There was also no difference between merging groups. Furthermore, there was no significant correlation between RBC 6TGN concentrations and the various biological parameters tested except for the mean erythrocyte volume. At 6 months, all patients of group 1 remained in remission and median RBC 6TGN concentration remained stable. No side effects were observed. Conclusions: There is, contrary to preliminary studies, a broad overlap in RBC 6TGN levels as well as for haematological parameters in patients in remission or not and responders or not to AZA/6-MP therapy. This suggests, beside a variability in the metabolism of these drugs, the existence of complex mechanisms of action. Nevertheless, beside the use of RBC 6TGN determination to confirm compliance to therapy, this dosage could be useful in non-responding patients, allowing, in absence of leukopenia, to increase the dose of AZA/6-MP safely.