Formation of CYP3A-specific metabolites of ibrutinib in vitro is correlated with hepatic CYP3A activity and 4β-hydroxycholesterol/cholesterol ratio.
Formation of CYP3A-specific metabolites of ibrutinib in vitro is correlated with hepatic CYP3A activity and 4β-hydroxycholesterol/cholesterol ratio.
复制标题
DOI：
10.1111/cts.13448
复制
发表时间：
2023-02
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
伊布替尼是一种口服布鲁顿酪氨酸激酶抑制剂，获批用于治疗B细胞恶性肿瘤，包括慢性淋巴细胞白血病。伊布替尼主要通过细胞色素P450（CYP）3A 4/5氧化代谢为M37（主要活性代谢产物）、M34和M25。本研究的目的是评估体外主要CYP 3A特异性伊克替尼代谢物的形成与肝脏CYP 3A活性和蛋白丰度之间的关系，并评价内源性CYP 3A生物标志物血浆4β-羟基胆固醇（4β-HC）与胆固醇比值预测具有匹配肝细胞的个体尸体供体中伊克替尼代谢物形成的效用。将伊布替尼（5 μM）与单供体人肝微粒体（n = 20）和原代人肝细胞（n = 15）孵育，并通过液相色谱-串联质谱分析测定代谢产物（M37、M34和M25）。通过定量靶向绝对蛋白质组学测定CYP 3A 4/5蛋白浓度，通过咪达唑仑1′-羟基化测定CYP 3A活性。人肝微粒体和肝细胞中伊布替尼代谢物的形成与咪达唑仑1 '-羟基化正相关。在从具有匹配肝细胞的相同15名供体中采集肝脏时，测量血浆样本中的血浆4β-HC和胆固醇浓度。肝细胞中咪达唑仑1′-羟基化与血浆4β-HC/胆固醇比值相关。当根据先前的个体发育研究排除婴儿供体（1岁）时，M37和M25形成与其余14名供体的血浆4β-HC/胆固醇比值相关（斯皮尔曼相关系数[r]分别为0.62和0.67）。总的来说，这些数据表明，在相同的非婴儿供体中，人肝细胞中CYP 3A特异性伊克替尼代谢物的形成、肝脏CYP 3A活性和血浆4β-HC/胆固醇比值之间呈正相关。
Ibrutinib is an orally administered Bruton's tyrosine kinase inhibitor approved for the treatment of B‐cell malignancies, including chronic lymphocytic leukemia. Ibrutinib is metabolized primarily via oxidation by cytochrome P450 (CYP) 3A4/5 to M37 (the primary active metabolite), M34, and M25. The objectives of this study were to assess the relationship between formation of the major CYP3A‐specific ibrutinib metabolites in vitro and hepatic CYP3A activity and protein abundance, and to evaluate the utility of the endogenous CYP3A biomarker, plasma 4β‐hydroxycholesterol (4β‐HC) to cholesterol ratio, to predict ibrutinib metabolite formation in individual cadaveric donors with matching hepatocytes. Ibrutinib (5 μM) was incubated with single‐donor human liver microsomes (n = 20) and primary human hepatocytes (n = 15), and metabolites (M37, M34, and M25) were measured by liquid chromatography‐tandem mass spectrometry analysis. CYP3A4/5 protein concentrations were measured by quantitative targeted absolute proteomics, and CYP3A activity was measured by midazolam 1′‐hydroxylation. Ibrutinib metabolite formation positively correlated with midazolam 1′‐hydroxylation in human liver microsomes and hepatocytes. Plasma 4β‐HC and cholesterol concentrations were measured in plasma samples obtained at the time of liver harvest from the same 15 donors with matching hepatocytes. Midazolam 1′‐hydroxylation in hepatocytes correlated with plasma 4β‐HC/cholesterol ratio. When an infant donor (1 year old) was excluded based on previous ontogeny studies, M37 and M25 formation correlated with plasma 4β‐HC/cholesterol ratio in the remaining 14 donors (Spearman correlation coefficients [r] 0.62 and 0.67, respectively). Collectively, these data indicate a positive association among formation of CYP3A‐specific ibrutinib metabolites in human hepatocytes, hepatic CYP3A activity, and plasma 4β‐HC/cholesterol ratio in the same non‐infant donors.
登录
查看更多内容
影响因子：
4.5
作者：
Gjestad, Caroline;Hole, Kristine;Molden, Espen
通讯作者：
Molden, Espen
影响因子：
30.8
作者：
Kuehl, P;Zhang, J;Schuetz, E
通讯作者：
Schuetz, E
影响因子：
3.4
作者：
de Vries, Ronald;Smit, Johan W.;de Jong, Jan
通讯作者：
de Jong, Jan
影响因子：
3.9
作者：
Bissada, Jennifer E.;Truong, Vivian;Jackson, Klarissa D.
通讯作者：
Jackson, Klarissa D.
影响因子：
3.6
作者：
Hines, Ronald N.
通讯作者：
Hines, Ronald N.