Jimmerson Leah C, Urban Thomas J, Truesdale Aimee, Baouchi-Mokrane Fafa, Kottilil Shyam, Meissner Eric G, Sims Zayani, Langness Jacob A, Hodara Ariel, Aquilante Christina L, Kiser Jennifer J
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
J Clin Pharmacol. 2017 Jan;57(1):118-124. doi: 10.1002/jcph.783. Epub 2016 Aug 4.
Individuals with lower inosine triphosphatase (ITPA) enzyme activity have a reduced likelihood of experiencing hemolytic anemia during hepatitis C virus (HCV) treatment containing ribavirin (RBV). Because ITPA degrades purines and RBV is a purine analogue, it is conceivable that ITPA activity may affect intracellular RBV concentrations. Here we assessed the association between ITPA activity phenotype and concentrations of RBV triphosphate (RBV-TP) in red blood cells (RBCs) during HCV treatment. RBV-TP was quantified in the RBCs of 177 HCV-infected individuals at a median (range) of 84 (19 to 336) days into HCV treatment that included RBV. Mean (SD) RBV-TP concentrations were 92.8 (51.6), 101.3 (53.5), 184.8 (84.5), and 197.7 (64.6) pmol/10 cells for 100%, 60%, 30%, and ≤10% ITPA activity groups, respectively. Overall, RBV-TP was approximately 2-fold higher in patients with ≤30% ITPA activity compared to 100% activity (P < .0001). Despite higher RBV-TP levels, individuals with variant ITPA phenotypes had less anemia. The 100% activity group had, on average, a -2.20 g/dL drop in hemoglobin vs -1.43 g/dL (P = .04) for 60% activity, -1.14 g/dL (P = .008) for 30% activity, and -0.70 g/dL (P = .06) for ≤10% activity. This finding of higher RBV-TP concentrations in RBCs in ITPA variants was unexpected given that ITPA activity-deficient individuals have a reduced likelihood of RBV-induced anemia. It also refutes the hypothesis that the mechanism by which ITPA variants are protected against anemia is due to lower RBV-TP levels in RBCs.
肌苷三磷酸酶（ITPA）活性较低的个体在接受含利巴韦林（RBV）的丙型肝炎病毒（HCV）治疗期间发生溶血性贫血的可能性降低。由于ITPA可降解嘌呤，而RBV是一种嘌呤类似物，因此可以推测ITPA活性可能会影响细胞内RBV浓度。在此，我们评估了HCV治疗期间ITPA活性表型与红细胞（RBC）中三磷酸利巴韦林（RBV-TP）浓度之间的关联。在接受含RBV的HCV治疗的第84天（范围为19至336天），对177例HCV感染个体的RBC中的RBV-TP进行了定量。对于ITPA活性为100%、60%、30%和≤10%的组，平均（标准差）RBV-TP浓度分别为92.8（51.6）、101.3（53.5）、184.8（84.5）和197.7（64.6）pmol/10⁶细胞。总体而言，与ITPA活性为100%的患者相比，ITPA活性≤30%的患者的RBV-TP约高2倍（P <.0001）。尽管RBV-TP水平较高，但ITPA表型变异的个体贫血程度较轻。ITPA活性为100%的组，血红蛋白平均下降-2.20 g/dL，而ITPA活性为60%的组为-1.43 g/dL（P = 0.04），30%活性组为-1.14 g/dL（P = 0.008），≤10%活性组为-0.70 g/dL（P = 0.06）。鉴于ITPA活性缺乏的个体发生RBV诱导的贫血的可能性降低，ITPA变异体的RBC中RBV-TP浓度较高这一发现出乎意料。这也反驳了ITPA变异体预防贫血的机制是由于RBC中RBV-TP水平较低的假设。
