Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA, Texas.
Texas Children's Hospital, Houston, USA, Texas.
Genet Med. 2018 Jul;20(7):708-716. doi: 10.1038/gim.2017.167. Epub 2017 Oct 12.
Benzoate and phenylbutyrate are widely used in the treatment of urea cycle disorders, but detailed studies on pharmacokinetics and comparative efficacy on nitrogen excretion are lacking.
We conducted a randomized, three-arm, crossover trial in healthy volunteers to study pharmacokinetics and comparative efficacy of phenylbutyrate (NaPB; 7.15 g•mBSA•day), benzoate (NaBz; 5.5 g•mBSA•day), and a combination of two medications (MIX arm; 3.575 g NaPB and 2.75 g NaBz•mBSA•day) on nitrogen excretion. Stable isotopes were used to study effects on urea production and dietary nitrogen disposal.
The conjugation efficacy for both phenylbutyrate and benzoate was 65%; conjugation was superior at the lower dose used in the MIX arm. Whereas NaPB and MIX treatments were more effective at excreting nitrogen than NaBz, nitrogen excretion as a drug conjugate was similar between phenylbutyrate and MIX arms. Nitrogen excreted per USD was higher with combination therapy compared with NaPB.
Phenylbutyrate was more effective than benzoate at disposing nitrogen. Increasing phenylbutyrate dose may not result in higher nitrogen excretion due to decreased conjugation efficiency at higher doses. Combinatorial therapy with phenylbutyrate and benzoate has the potential to significantly decrease treatment cost without compromising the nitrogen disposal efficacy.
苯甲酸钠和苯丁酸钠被广泛用于治疗尿素循环障碍，但关于其药代动力学和氮排泄比较疗效的详细研究尚缺乏。
我们在健康志愿者中进行了一项随机、三臂、交叉试验，以研究苯丁酸钠（NaPB；7.15 g·mBSA·天）、苯甲酸钠（NaBz；5.5 g·mBSA·天）和两种药物联合用药（MIX 组；3.575 g NaPB 和 2.75 g NaBz·mBSA·天）在氮排泄方面的药代动力学和比较疗效。稳定同位素用于研究对尿素生成和饮食氮处理的影响。
苯丁酸钠和苯甲酸钠的结合效率均为 65%；MIX 组中使用的较低剂量的结合效果更好。虽然 NaPB 和 MIX 治疗在排泄氮方面比 NaBz 更有效，但作为药物结合物排泄的氮在苯丁酸钠和 MIX 组之间相似。与 NaPB 相比，联合治疗每美元排泄的氮更多。
苯丁酸钠在排泄氮方面比苯甲酸钠更有效。由于高剂量时结合效率降低，增加苯丁酸钠剂量可能不会导致更高的氮排泄。苯丁酸钠和苯甲酸钠的联合治疗具有降低治疗成本的潜力，同时不影响氮排泄效果。
