Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease
Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease
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DOI：
10.1111/j.1528-1157.1999.tb00778.x
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发表时间：
1999-06-01
期刊：
影响因子：
5.6
通讯作者：
Alldredge, BK
中科院分区：
文献类型：
--
作者：
Aweeka, FT;Gottwald, MD;Alldredge, BK
目的：研究苯妥英钠（PHT）水溶性前体药物磷苯妥英钠（FOS）在正常人体内的药代动力学行为。这是第一次研究肝脏或肾脏疾病的影响的速度和程度的转换FOS PHT.Methods：单剂量的磷苯妥英（250毫克，在30分钟的时间内）与肝硬化（n = 4），肾脏疾病，需要维持性血液透析（n = 4），和健康对照组（n = 4）。结果：三组达到血药峰浓度的平均时间相似。然而，肝脏或肾脏疾病组达到PHT血浆峰浓度的平均时间往往早于健康受试者。三组FOS的半衰期分别为4.5、9.2和9.5 min。在患有肝脏或肾脏疾病的受试者中，FOS清除率有增加的趋势，PHT峰值浓度也有提前的趋势。这一发现与FOS与血浆蛋白结合减少和未结合FOS分数增加一致，这是由于与这些疾病状态相关的血浆蛋白浓度降低所致。转换的FOS PHT是同样有效的受试者与肝脏或肾脏疾病和健康subjects.Conclusions：虽然三组之间的药代动力学参数的差异没有统计学意义，这些数据表明，需要密切的临床监测期间FOS管理肝脏或肾脏疾病的患者。为了最大限度地减少该患者人群中不良反应的发生率，FOS可能需要以较低的剂量给药或更缓慢地输注。
Purpose: The pharmacokinetic behavior of fosphenytoin (FOS), the water-soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT.Methods: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). Serial plasma concentrations were measured, and pharmacokinetic parameters were calculated.Results: The mean time to reach the peak plasma FOS concentration was similar for each of the three groups. However, the mean time to achieve peak plasma concentrations of PHT tended to occur earlier in the hepatic or renal disease groups than in healthy subjects. The half-life of FOS was 4.5, 9.2, and 9.5 min for the three groups, respectively. There was a trend toward increased FOS clearance and earlier peak PHT concentration in subjects with hepatic or renal disease. This finding is consistent with decreased binding of FOS to plasma proteins and increased fraction of unbound FOS resulting from decreased plasma protein concentrations associated with these disease states. The conversion of FOS to PHT was equally efficient in subjects with hepatic or renal disease and healthy subjects.Conclusions: Although the differences in pharmacokinetic parameters between the three groups were not statistically significant, these data suggest the need for close clinical monitoring during FOS administration to patients with hepatic or renal disease. To minimize the incidence of adverse effects in this patient population, FOS may need to be administered at lower doses or infused more slowly.