Pai Amy Barton, Norenberg Jeffrey, Boyd Alex, Raj Dominic, Chan Lingtak-Neander
University of New Mexico College of Pharmacy, MSC09 5360, Albuquerque, NM 87131, USA.
Clin Ther. 2007 Dec;29(12):2699-705. doi: 10.1016/j.clinthera.2007.12.024.
Cytochrome P450 (CYP) 3A4 is an enzyme with activity dependent on the reduction of heme iron that is responsible for the metabolism of many drugs. CYP3A4 activity is reduced in hemodialysis (HD) patients and thus may be related to functional iron deficiency.
The purpose of this study was to investigate the effect of IV iron supplementation on hepatic is CYP3A4 activity in HD patients.
This prospective, open-label study was conducted in 12 iron-deficient (transferrin saturation <20% or ferritin <100 ng/L) HD patients on stable medication regimens. To probe for hepatic CYP3A4 activity, an erythromycin breath test (ERMBT) was administered before and after 1 g IV iron sucrose (administered as a 100-mg dose [20 mg/mL]), at each of 10 consecutive HD sessions). CYP3A4 activity was estimated by the percentage of administered (14)C exhaled in a single-breath collection after the test dose of erythromycin underwent demethylation by CYP3A4. The ERMBT was also administered to 7 age-, sex-, and race-matched healthy controls.
Twelve HD patients (6 Hispanic, 3 white, 3 Native American; 8 men, 4 women; mean [SEM] age, 56.2 [5.0] years; mean [SEM] weight, 77.0 [5.6] kg; and 7 controls (4 men, 3 women; mean [SEM] age, 51.3 [5.0] years; mean [SEM] weight, 77.5 [7.4] kg) were enrolled in the study. In the total HD population studied, mean (SEM) CYP3A4 activity did not change significantly after IV iron replacement (1.46 [0.27] vs 1.57 [0.24] (14)C exhaled/h). A subgroup of 7 HD patients had significantly lower CYP3A4 activity before IV iron replacement compared with the other 5 HD patients and controls (mean [SEM] 0.86 [0.24] vs 2.30 [0.26] and 2.10 [0.26] (14)C exhaled/h; P < 0.01). After IV iron replacement, mean (SEM) CYP3A4 activity increased in these 7 HD patients (120.1% [67.1%]); P = 0.04) and it was not statistically different from that of controls (1.50 [0.36] vs 2.10 [0.26]).
Overall, IV iron administration had no significant effect on hepatic CYP3A4 activity. However, in a subset of HD patients with low baseline CYP3A4 activity indicated by low ERMBT values, IV iron supplementation was associated with a potentially clinically relevant increase in hepatic CYP3A4 activity. Further studies are needed to clarify mechanisms and clinical implications of this interaction.
细胞色素P450（CYP）3A4是一种其活性依赖于血红素铁还原的酶，负责多种药物的代谢。血液透析（HD）患者的CYP3A4活性降低，因此可能与功能性铁缺乏有关。
本研究旨在探讨静脉补铁对HD患者肝脏CYP3A4活性的影响。
本前瞻性、开放标签研究纳入了12例铁缺乏（转铁蛋白饱和度<20%或铁蛋白<100 ng/L）且用药方案稳定的HD患者。为检测肝脏CYP3A4活性，在连续10次HD治疗期间，每次均于静脉注射1 g蔗糖铁（以100 mg剂量[20 mg/mL]给药）前后进行红霉素呼气试验（ERMBT）。CYP3A4活性通过在试验剂量的红霉素经CYP3A4去甲基化后单次呼气收集的呼出（14）C的百分比来估算。还对7名年龄、性别和种族匹配的健康对照者进行了ERMBT。
本研究纳入了12例HD患者（6例西班牙裔、3例白人、3例美洲原住民；8例男性，4例女性；平均[标准误]年龄56.2[5.0]岁；平均[标准误]体重77.0[5.6]kg）和7名对照者（4例男性，3例女性；平均[标准误]年龄51.3[5.0]岁；平均[标准误]体重77.5[7.4]kg）。在整个研究的HD患者群体中，静脉补铁后平均（标准误）CYP3A4活性无显著变化（呼出（14）C/h为1.46[0.27] vs 1.57[0.24]）。7例HD患者亚组在静脉补铁前的CYP3A4活性显著低于其他5例HD患者和对照者（呼出（14）C/h平均[标准误]为0.86[0.24] vs 2.30[0.26]和2.10[0.26]；P<0.01）。静脉补铁后，这7例HD患者的平均（标准误）CYP3A4活性增加（120.1%[67.1%]）；P = 0.04），且与对照者无统计学差异（1.50[0.36] vs 2.10[0.26]）。
总体而言，静脉补铁对肝脏CYP3A4活性无显著影响。然而，在ERMBT值较低表明基线CYP3A4活性较低的部分HD患者中，静脉补铁与肝脏CYP3A4活性的潜在临床相关增加有关。需要进一步研究来阐明这种相互作用的机制和临床意义。
