尿素循环障碍(UCDs),肝细胞代谢的先天性错误,导致高氨血症并导致神经认知缺陷,昏迷,甚至死亡。4-苯基丁酸钠(NaPB),UCD的标准辅助疗法,通过谷氨酰胺消耗产生氮沉积的替代途径。餐后或餐后立即给药是NaPB的批准用法。然而,我们以前发现,在健康成人和儿童肝内胆汁淤积症患者中,餐前口服能增强其效力.本研究评估了食物对5例UCD患者NaPB药代动力学和药效学的影响。经过一夜的禁食,NaPB以75mg/kg/剂口服给药(高剂量,HD)或25mg/kg/剂(低剂量,LD)早餐前15分钟或早餐后立即。每个患者用这四种NaPB治疗方案进行治疗。无论哪种剂量,早餐前给药而不是早餐后给药显着增加了血浆PB水平,并降低了血浆谷氨酰胺的利用率。早餐前LD给药导致血浆谷氨酰胺可用性的衰减大于早餐后HD给药。在所有测试方案中,支链氨基酸的血浆水平降低至相同程度。在这项研究中没有发生严重的不良事件。总之,餐前口服NaPB可使PB的全身暴露最大化,从而对UCD患者的谷氨酰胺消耗有效。
Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, cause hyperammonemia and lead to neurocognitive deficits, coma, and even death. Sodium 4-phenylbutyrate (NaPB), a standard adjunctive therapy for UCDs, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the approved usage of NaPB. However, we previously found that preprandial oral administration enhanced its potency in healthy adults and pediatric patients with intrahepatic cholestasis. The present study evaluated the effect of food on the pharmacokinetics and pharmacodynamics of NaPB in five patients with UCDs. Following an overnight fast, NaPB was administered orally at 75 mg/kg/dose (high dose, HD) or 25 mg/kg/dose (low dose, LD) either 15 min before or immediately after breakfast. Each patient was treated with these four treatment regimens with NaPB. With either dose, pre-breakfast administration rather than post-breakfast administration significantly increased plasma PB levels and decreased plasma glutamine availability. Pre-breakfast LD administration resulted in a greater attenuation in plasma glutamine availability than post-breakfast HD administration. Plasma levels of branched-chain amino acids decreased to the same extent in all tested regimens. No severe adverse events occurred during this study. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of PB and thereby its efficacy on glutamine consumption in patients with UCDs.