Department of Clinical Pharmacy, Oita University Hospital, 1-1 Hasama-machi, Oita, 879-5593, Japan; Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
Department of Clinical Pharmacy, Oita University Hospital, 1-1 Hasama-machi, Oita, 879-5593, Japan.
Pharmacol Rep. 2019 Apr;71(2):276-281. doi: 10.1016/j.pharep.2018.12.007. Epub 2018 Dec 15.
Phenoconversion is a phenomenon whereby some genotypic extensive metabolizers transiently exhibit drug metabolizing enzyme activity at similar level as that of poor metabolizers. Renal failure is known to decrease CYP3A activity in humans. Indoxyl sulfate, parathyroid hormone (PTH), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) have been reported to cause CYP3A downregulation in renal failure. We measured plasma concentrations of the above compounds in stable kidney transplant recipients, and evaluated their relations with phenoconversion of CYP3A evaluated by plasma concentration of 4β-hydroxycholesterol, a biomarker of CYP3A activity. Phenoconversion was defined as a genotypic extensive/intermediate metabolizer exhibiting CYP3A activity below the cutoff value that discriminates extensive/intermediate from poor metabolizers.
Sixty-three Japanese kidney transplant recipients who underwent transplantation more than 180 days prior to the study were included. Morning blood samples were collected, and CYP3A5 polymorphism as well as plasma concentrations of 4β-hydroxycholesterol, indoxyl sulfate, intact-PTH, IL-6 and TNF-α were determined.
Significantly higher plasma 4β-hydroxycholesterol concentration was observed in recipients with CYP3A51 allele (n = 23) compared to those without the allele (n = 40), and the cut-off value was 40.0 ng/mL. Ten recipients with CYP3A51 allele exhibited CYP3A activity below 40.0 ng/mL (phenoconversion). Only plasma indoxyl sulfate concentration was significantly higher in recipients with CYP3A phenoconversion compared to those without phenoconversion.
These findings suggest that higher plasma indoxyl sulfate concentration may be involved in CYP3A phenoconversion. Dose adjustment of drugs metabolized by CYP3A may be needed in patients with CYP3A5*1 allele and high blood indoxyl sulfate.
表型转化是一种现象，即一些基因型广泛代谢者会暂时表现出与弱代谢者相似水平的药物代谢酶活性。已知肾衰竭会降低人类 CYP3A 的活性。已经报道了硫酸吲哚酚、甲状旁腺激素（PTH）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）会导致肾衰竭时 CYP3A 的下调。我们测量了稳定的肾移植受者的血浆中上述化合物的浓度，并评估了它们与 CYP3A 表型转化的关系，CYP3A 表型转化由 CYP3A 活性的生物标志物 4β-羟胆固醇的血浆浓度来评估。表型转化定义为基因型广泛/中间代谢者表现出低于区分广泛/中间代谢者和弱代谢者的截止值的 CYP3A 活性。
纳入了 63 名在研究前 180 天以上接受过移植的日本肾移植受者。采集清晨血样，并测定 CYP3A5 多态性以及 4β-羟胆固醇、硫酸吲哚酚、完整 PTH、IL-6 和 TNF-α 的血浆浓度。
与无 CYP3A51 等位基因（n=40）的受者相比，携带 CYP3A51 等位基因（n=23）的受者的血浆 4β-羟胆固醇浓度显著升高，且截止值为 40.0ng/ml。10 名携带 CYP3A5*1 等位基因的受者的 CYP3A 活性低于 40.0ng/ml（表型转化）。仅在 CYP3A 表型转化的受者中，血浆硫酸吲哚酚浓度显著高于无表型转化的受者。
这些发现表明，较高的血浆硫酸吲哚酚浓度可能与 CYP3A 表型转化有关。对于携带 CYP3A5*1 等位基因和高血硫酸吲哚酚的患者，可能需要调整由 CYP3A 代谢的药物的剂量。
