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.

尿素循环障碍 (UCD)，即肝细胞代谢的先天性错误，会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) 是 UCD 的标准辅助疗法，通过消耗谷氨酰胺产生氮沉积的替代途径。餐中或餐后立即给药是 NaPB 的批准用法。然而，我们之前发现餐前口服给药可增强其在健康成人和肝内胆汁淤积儿童患者中的效力。本研究评估了食物对五名 UCD 患者 NaPB 药代动力学和药效学的影响。禁食过夜后，在早餐前 15 分钟或早餐后立即以 75 毫克/公斤/剂量（高剂量，HD）或 25 毫克/公斤/剂量（低剂量，LD）口服 NaPB。每位患者均接受这四种 NaPB 治疗方案。对于任一剂量，早餐前给药而不是早餐后给药显着增加血浆 PB 水平并降低血浆谷氨酰胺可用性。与早餐后 HD 给药相比，早餐前 LD 给药导致血浆谷氨酰胺可用性的更大衰减。在所有测试方案中，支链氨基酸的血浆水平降低到相同程度。本研究期间未发生严重不良事件。总之，餐前口服 NaPB 可使 PB 的全身暴露最大化，从而提高其对 UCD 患者谷氨酰胺消耗的疗效。早餐前给药而不是早餐后给药显着增加血浆 PB 水平并降低血浆谷氨酰胺可用性。与早餐后 HD 给药相比，早餐前 LD 给药导致血浆谷氨酰胺可用性的更大衰减。在所有测试方案中，支链氨基酸的血浆水平降低到相同程度。本研究期间未发生严重不良事件。总之，餐前口服 NaPB 可使 PB 的全身暴露最大化，从而提高其对 UCD 患者谷氨酰胺消耗的疗效。早餐前给药而不是早餐后给药显着增加血浆 PB 水平并降低血浆谷氨酰胺可用性。与早餐后 HD 给药相比，早餐前 LD 给药导致血浆谷氨酰胺可用性的更大衰减。在所有测试方案中，支链氨基酸的血浆水平降低到相同程度。本研究期间未发生严重不良事件。总之，餐前口服 NaPB 可使 PB 的全身暴露最大化，从而提高其对 UCD 患者谷氨酰胺消耗的疗效。在所有测试方案中，支链氨基酸的血浆水平降低到相同程度。本研究期间未发生严重不良事件。总之，餐前口服 NaPB 可使 PB 的全身暴露最大化，从而提高其对 UCD 患者谷氨酰胺消耗的疗效。在所有测试方案中，支链氨基酸的血浆水平降低到相同程度。本研究期间未发生严重不良事件。总之，餐前口服 NaPB 可使 PB 的全身暴露最大化，从而提高其对 UCD 患者谷氨酰胺消耗的疗效。