Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration
Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration
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DOI：
10.1016/j.ymgme.2003.09.014
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发表时间：
2004-01-01
影响因子：
3.8
通讯作者：
Blau, N
中科院分区：
文献类型：
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作者：
Fiege, B;Ballhausen, D;Blau, N
四氢生物蝶呤（BH4）被广泛用作BH4缺乏和轻度苯丙酮尿症（PKU）患者的治疗剂，在心血管疾病患者中测量其血浆浓度的需求日益增加。我们使用差碘氧化法测量了四名成年人口服BH4（2、10和20 mg/kg体重）后二硫赤藓糖醇（DTE）预处理血浆中的BH4和总生物蝶呤。在血液取样后立即分析，发现约80%（范围64.8-92.2%）的总生物蝶呤为BH4。与作为抗坏血酸的抗氧化剂相比，DTE对BH4的氧化更有保护作用，特别是在储存超过8个月的样品中。在不添加抗氧化剂（DTE或抗坏血酸）的情况下，几乎没有检测到BH4。测定不同时间间隔（口服后33 h） BH4和总生物蝶呤的含量，并估计药代动力学参数T-max （1 ~ 4 h）、C-max （10 mg/kg剂量下生物蝶呤258.7 ~ 259.0 nmol/L）和曲线下面积（AUC=1708 ~ 1958 nmol*h/L ~ T=10 h）。BH4的消除半衰期为3.3-5.1 h。与口服给药相比，BH4剂量加倍至20 mg/kg导致AUC增加60%，而舌下给药（2 mg/kg）导致BH4血浆浓度增加58-76%。这些初步数据表明，在BH4辅助因子缺陷和BH4反应性苯丙氨酸羟化酶缺乏症患者中，BH4应每天至少给予2至3次剂量，舌下给药可能降低所需的BH4剂量，从而降低治疗成本。由于个体间药代动力学特性的差异，在一些高苯丙氨酸血症和轻度PKU患者中，血浆BH4水平可能不足以充分激活肝脏苯丙氨酸羟化酶，从而降低血液苯丙氨酸水平。评估血浆BH4或总生物蝶呤浓度可能是控制负荷试验效果的好方法。(C) 2003 Elsevier Inc.版权所有。
Tetrahydrobiopterin (BH4) is widely used as a therapeutic agent in patients with BH4 deficiencies and mild forms of phenylketonuria (PKU) and there is an increasing need for the measurement of its plasma concentrations in patients with cardiovascular disorders. We measured BH4 and total biopterin in dithioerythritol (DTE) pretreated plasma from four adults after oral administration of BH4 (2, 10, and 20 mg/kg body weight) using the differential iodine oxidation method. About 80% (range 64.8-92.2%) of total biopterin was found as BH4 when analyzed immediately after blood sampling. Compared with ascorbic acid as an antioxidant, DTE was more protective against oxidation of BH4, particularly in samples stored over a period of 8 months. Without antioxidant (DTE or ascorbic acid) almost no BH4 was detected. Furthermore, BH4 and total biopterin were measured at different time intervals (up to 33 h after oral administration) and pharmacokinetic parameters T-max (1-4 h), C-max (258.7-259.0 nmol/L biopterin at a dosage of 10 mg/kg), and area under the curve (AUC=1708-1958 nmol*h/L up to T=10 h) were estimated. The elimination half-life time was calculated to be 3.3-5.1 h. Doubling the BH4 dosage to 20 mg/kg resulted in 60% higher AUC while sublingual BH4 application (2 mg/kg) resulted in 58-76% higher BH4 plasma concentrations when compared with oral administration. These preliminary data suggest that in patients with BH4 cofactor defects and BH4-responsive phenylalanine hydroxylase deficiency, BH4 should be given in at least two to three daily doses and that sublingual administration may lower the required BH4 dosage and subsequently the cost of treatment. Due to inter individual differences in pharmacokinetic properties, in some patients with hyperphenylalaninemia and mild PKU plasma BH4 levels may be not high enough to fully activate the liver phenylalanine hydroxylase and thus lower blood phenylalanine levels. Assessment of plasma BH4 or total biopterin concentrations may be a good way to control the efficacy of the loading test. (C) 2003 Elsevier Inc. All rights reserved.