测量4-hydroxylation异环磷酰胺的人类肝脏微粒体使用自由的估计和蛋白结合的丙烯醛和酮和carboxyifosfamide共同决策制。

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施密特Preiss R, R,鲍曼F, Hanschmann H, haus J,盖斯勒F, Pahlig H, Ratzewiss B

测量4-hydroxylation异环磷酰胺的人类肝脏微粒体使用自由的估计和蛋白结合的丙烯醛和酮和carboxyifosfamide共同决策制。

J癌症Res肿瘤防治杂志。2002年7月,128 (7):385 - 92。Epub 2002年6月11日。

PubMed ID

12136253 (在PubMed

]

文摘

目的:本研究的目的是确定异环磷酰胺的营业额(4-hydroxylation和N-dechloroethylation)共有25人肝微粒体准备的共同决策制酮和carboxyifosfamide以及计算自由和蛋白结合的丙烯醛进行了第一次。方法:异环磷酰胺的4-hydroxylation估计用丙烯醛(免费和蛋白结合的)和新开发过程涉及的共同决策制酮和carboxyifosfamide (LC / MS)。异环磷酰胺N-dechloroethylation被确定为2 -和3-dechloroethylifosfamide (LC / MS)。结果:使用通常的估计解放自由丙烯醛25人肝微粒体的准备,异环磷酰胺的4-hydroxylation达0.28 + / - -0.16 nmol /分钟。纳摩(P450)。然而,在计算4-hydroxylation免费的总和和蛋白结合的丙烯醛、酮和carboxyifosfamide高出九倍活动(2.40 + / - -0.73 nmol /分钟。纳摩(P450))被发现。不活跃的代谢产物酮的比例(25/25)和carboxyifosfamide (5/25) 4-hydroxylation只相当于0.79 - -5.25%(平均2.90%)。异环磷酰胺N-dechloroethylation(平均0.21 + / - -0.11 nmol /分钟。纳摩(P450))决定的和2 -和3-dechloroethylifosfamide估计为8.3 + /异环磷酰胺总营业额的-4.3%。 The application of the relative substrate-activity factor (RSF)-approach and the calculation of the contribution of various isoforms in the ifosfamide 4-hydroxylation yielded the following results: CYP 3A4: 58+/-31%, CYP 2A6: 25+/-15%, and CYP 2C9: 5+/-2% of the total measured 4-hydroxylation. A correlation between 4-hydroxylation and the N-dechloroethylation rates of ifosfamide and the activities of isoenzymes indicates the involvement of both CYP 3A4 ( P=0.026) and CYP 2C9 ( P=0.012) in the 4-hydroxylation reaction and of CYP 3A4 ( P<0.01) in the N-dechloroethylation reaction. CONCLUSIONS: The estimation of protein-bound acrolein should be included in the calculation of the ifosfamide 4-hydroxylation besides liberated free acrolein. Because of the small amounts of the inactive metabolites keto- and carboxyifosfamide, the exclusive determination of acrolein only (free and protein-bound) seems to suffice for the calculation of total ifosfamide hydroxylation. Using this method the hepatic in vitro turnover of ifosfamide was estimated as 92% for 4-hydroxylation (CYP 3A4 and CYP 2A6 mediated) and 8% for N-dechloroethylation (CYP 3A4 mediated), and in this way, a relative overestimation of the N-dechloroethylation of ifosfamide on the whole metabolism is avoided.

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药物酶

药物	酶	类	生物	药理作用	行动
环磷酰胺	细胞色素P450 2 b6	蛋白质	人类	未知的	底物 诱导物	细节
环磷酰胺	细胞色素P450 3 a4	蛋白质	人类	未知的	底物 诱导物	细节
异环磷酰胺	细胞色素P450 3 a4	蛋白质	人类	未知的	底物 抑制剂 诱导物	细节