Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders

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 consu...

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Main Authors: Yoko Nakajima, Shuhei Osaka, Tadahaya Mizuno, Katsuyuki Yokoi, Satoshi Nakano, Saeko Hirai, Yuka Hiraoka, Yoshiki Miura, Mitsuyoshi Suzuki, Hiroyuki Kusuhara, Hisamitsu Hayashi
Format: Article
Language:English
Published: Elsevier 2021-12-01
Series:Molecular Genetics and Metabolism Reports
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2214426921000938
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author Yoko Nakajima
Shuhei Osaka
Tadahaya Mizuno
Katsuyuki Yokoi
Satoshi Nakano
Saeko Hirai
Yuka Hiraoka
Yoshiki Miura
Mitsuyoshi Suzuki
Hiroyuki Kusuhara
Hisamitsu Hayashi
author_facet Yoko Nakajima
Shuhei Osaka
Tadahaya Mizuno
Katsuyuki Yokoi
Satoshi Nakano
Saeko Hirai
Yuka Hiraoka
Yoshiki Miura
Mitsuyoshi Suzuki
Hiroyuki Kusuhara
Hisamitsu Hayashi
author_sort Yoko Nakajima
collection DOAJ
description 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.
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spelling doaj.art-bd2ef431f75b4e2fb94027b6644be2282022-12-21T21:46:29ZengElsevierMolecular Genetics and Metabolism Reports2214-42692021-12-0129100799Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disordersYoko Nakajima0Shuhei Osaka1Tadahaya Mizuno2Katsuyuki Yokoi3Satoshi Nakano4Saeko Hirai5Yuka Hiraoka6Yoshiki Miura7Mitsuyoshi Suzuki8Hiroyuki Kusuhara9Hisamitsu Hayashi10Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, JapanLaboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, JapanLaboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, JapanDepartment of Pediatrics, Fujita Health University School of Medicine, Toyoake, JapanDepartment of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, JapanDepartment of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, JapanLaboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, JapanLaboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, JapanDepartment of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, JapanLaboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, JapanLaboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan; Corresponding author at: Laboratory of Molecular Pharmacokinetics, Department of Medical Pharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.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.http://www.sciencedirect.com/science/article/pii/S2214426921000938Amino acidsClinical studyPharmacokineticsUrea cycle disorders
spellingShingle Yoko Nakajima
Shuhei Osaka
Tadahaya Mizuno
Katsuyuki Yokoi
Satoshi Nakano
Saeko Hirai
Yuka Hiraoka
Yoshiki Miura
Mitsuyoshi Suzuki
Hiroyuki Kusuhara
Hisamitsu Hayashi
Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders
Molecular Genetics and Metabolism Reports
Amino acids
Clinical study
Pharmacokinetics
Urea cycle disorders
title Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders
title_full Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders
title_fullStr Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders
title_full_unstemmed Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders
title_short Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders
title_sort influence of food on pharmacokinetics and pharmacodynamics of 4 phenylbutyrate in patients with urea cycle disorders
topic Amino acids
Clinical study
Pharmacokinetics
Urea cycle disorders
url http://www.sciencedirect.com/science/article/pii/S2214426921000938
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