Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.
Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.
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DOI：
10.1002/hep.23589
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发表时间：
2010-06
期刊：
影响因子：
13.5
通讯作者：
Scharschmidt, Bruce F.
中科院分区：
文献类型：
--
作者：
McGuire, Brendan M.;Zupanets, Igor A.;Lowe, Mark E.;Xiao, Xunjun;Syplyviy, Vasyliy A.;Monteleone, Jon;Gargosky, Sharron;Dickinson, Klara;Martinez, Antonia;Mokhtarani, Masoud;Scharschmidt, Bruce F.
苯丁酸（PBA）作为苯丁酸钠（NaPBA）被批准用于治疗尿素循环障碍（UCD），通过PBA衍生的苯乙酸与谷氨酰胺结合形成苯乙酰谷氨酰胺（PAGN）介导废氮排泄，并经尿液排泄。苯丁酸甘油酯（GPB）是PBA的液体甘油三酯前体药物，不含钠，具有良好的适口性，正在研究用于治疗肝性脑病（HE）。已经进行了体外和临床研究，以评估GPB在健康成人和肝硬化个体中的消化、安全性和药理学。通过pH滴定的方式在体外测量GPB水解。24名健康成人接受GPB和NaPBA单次给药，8名健康成人和24名糖尿病受试者接受GPB单日和多日给药，并在血液和尿液中测定代谢物。进行模拟以评估较高水平的GPB给药。GPB被人胰甘油三酯脂肪酶、胰脂肪酶相关蛋白2和羧酸酯脂肪酶水解。临床安全性满意。与NaPBA相比，GPB的血药浓度峰值出现较晚且较低;尿PAGN排泄相似，但需要更长时间。NaPBA和GPB均在4天内达到稳态;在血液或尿液中未检测到完整的GPB。肝硬化受试者将GPB转化为PAGN与健康成人相似。模拟结果表明，GPB可以安全地以相当于UCD最高批准NaPBA剂量的水平施用于阿尔茨海默病受试者。GPB表现出延迟释放特性，可能反映了胰腺脂肪酶逐渐释放PBA，并且在肝硬化成人中耐受良好，这表明有必要对HE进行进一步的临床试验。
Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.
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影响因子：
3.6
作者：
Armand, M;Hamosh, M;Hamosh, P
通讯作者：
Hamosh, P
DOI：
10.1097/00005176-199104000-00006
发表时间：
1991-04-01
影响因子：
2.9
作者：
BOEHM, G;BIERBACH, U;RAIHA, NCR
通讯作者：
RAIHA, NCR
影响因子：
1.6
作者：
Cordle, RA;Lowe, ME
通讯作者：
Lowe, ME
影响因子：
6.5
作者：
D'Silva, Sheryl;Xiao, Xunjun;Lowe, Mark E.
通讯作者：
Lowe, Mark E.
DOI：
10.1136/fn.80.3.f183
发表时间：
1999-05-01
影响因子：
4.4
作者：
Manson, WG;Coward, WA;Weaver, LT
通讯作者：
Weaver, LT