Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis

Nakano, Satoshi; Osaka, Shuhei; Sabu, Yusuke; Minowa, Kei; Hirai, Saeko; Kondou, Hiroki; Kimura, Takeshi; Azuma, Yoshihiro; Watanabe, Satoshi; Inui, Ayano; Bessho, Kazuhiko; Nakamura, Hidefumi; Kusano, Hironori; Nakazawa, Atsuko; Tanikawa, Ken; Kage, Masayoshi; Shimizu, Toshiaki; Kusuhara, Hiroyuki; Zen, Yoh; Suzuki, Mitsuyoshi; Hayashi, Hisamitsu

doi:10.1038/s41598-019-53628-x

Cited by 9 publications

(14 citation statements)

References 32 publications

(43 reference statements)

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“…However, in a small study in 7 patients with PFIC-1 and -2 treated with 4-PBA no adverse events were reported even after dose escalation. 95 Correction and restoration of the activity of ABCB4 variants, although in vitro, provide interesting leads in the context of personalised medicine. Recently, ivacaftora cystic fibrosis transmembrane conductance regulator (CFTR) potentiatorwas shown to rescue defective phosphatidylcholine secretion activity.…”

Section: Key Pointmentioning

confidence: 99%

Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults

Stättermayer

Halilbasic

Wrba

et al. 2020

Journal of Hepatology

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The ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 encodes the ABCB4 protein (alias multidrug resistance protein 3 [MDR3]), a P-glycoprotein in the canalicular membrane of the hepatocytes that acts as a translocator of phospholipids into bile. Several variants in ABCB4 have been shown to cause ABCB4 deficiency, accounting for a disease spectrum ranging from progressive familial cholestasis type 3 to less severe conditions like low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy or drug-induced liver injury. Furthermore, whole genome sequencing has shown that ABCB4 variants are associated with an increased incidence of gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis or elevated liver function tests. Diagnosis of ABCB4 deficiency-related diseases is based on clinical presentation, serum biomarkers, imaging techniques, liver histology and genetic testing. Nevertheless, the clinical presentation can vary widely and clear genotypephenotype correlations are currently lacking. Ursodeoxycholic acid is the most commonly used medical treatment, but its efficacy has yet to be proven in large controlled clinical studies. Future pharmacological options may include stimulation/restoration of residual function by chaperones (e.g. 4-phenyl butyric acid, curcumin) or induction of ABCB4 transcription by FXR (farnesoid X receptor) agonists or PPARa (peroxisome proliferator-activated receptor-a)-ligands/fibrates. Orthotopic liver transplantation remains the last and often only therapeutic option in cirrhotic patients with end-stage liver disease or patients with intractable pruritus.

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Section: Key Pointmentioning

confidence: 99%

Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults

Stättermayer

Halilbasic

Wrba

et al. 2020

Journal of Hepatology

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“…The last patient showed no clear response to NaPB therapy in the first 12 months. Therefore, the regimen was switched to preprandial oral administration, and the beneficial effects of NaPB therapy were observed . The change in the liver histology of this patient in the first 12 months after the beginning of NaPB therapy was determined as “deteriorated” by all pathologists, but in the next 12 months it was evaluated as “unchanged” by two pathologists and “improved” by the other (Table S4; see Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

“…The period between each biopsy was 12 months. Their detailed clinical courses have been published elsewhere . One patient showed a good clinical response to NaPB with improved serological findings, including bilirubin, while the other showed no obvious improvement in 12 months after starting postprandial oral administration of NaPB.…”

Section: Methodsmentioning

confidence: 99%

Proposal of a liver histology‐based scoring system for bile salt export pump deficiency

Zen

Kondou

Nakazawa

et al. 2020

Hepatology Research

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Aim Bile salt export pump (BSEP) deficiency manifests a form of progressive intrahepatic cholestasis. This study aimed to establish a scoring system of liver histology for the uncommon genetic condition. Methods After a roundtable discussion and histology review, a scoring system for BSEP deficiency was established. Eleven tissue samples were independently evaluated by three pathologists based on the proposed standard for an interobserver agreement analysis. In four cases with serial tissue samples available, correlation between changes in histology scores and clinical outcome was examined. Results Of 14 initially listed histopathological findings, 12 were selected for scoring and grouped into the following four categories: cholestasis, parenchymal changes, portal tract changes and fibrosis. Each category consisted of two to four microscopic findings that were further divided into three to six scores; therefore, each category had a maximum score of 8–11. Interobserver agreement was highest for pericellular fibrosis (κ = 0.849) and lowest for hepatocellular cholestasis (κ = 0.241) with the mean and median κ values of the 12 parameters being 0.561 and 0.602, respectively. For two patients whose clinical features worsened, score changes between two time points were interpreted as deteriorated. In two patients, who showed a good clinical response to preprandial treatment with sodium 4‐phenylbutyrate, histological changes were evaluated as improved or unchanged. Conclusions The proposed histology‐based scoring system for BSEP deficiency with moderate interobserver agreement may be useful not only for monitoring microscopic changes in clinical practice but also for a surrogate endpoint in clinical trials.

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“…Pre-breakfast, rather than post-breakfast, oral administration markedly increased systemic exposure of PB and decreased plasma glutamine availability after breakfast in the healthy adults [6] . In the pediatric patients with PFIC, we found that food intake before oral administration of NaPB reduced plasma PB levels and diminished its therapeutic efficacy through a choleretic effect [7] , another pharmacological action of NaPB [10] , [11] , [12] . Importantly, there were no severe adverse events attributable to preprandial oral administration of NaPB.…”

Section: Introductionmentioning

confidence: 84%

“…We have identified an interaction between NaPB and food in healthy adults [6] and in pediatric patients with progressive familial intrahepatic cholestasis (PFIC) [7] , a rare inherited autosomal recessive liver disease [8] , [9] . Pre-breakfast, rather than post-breakfast, oral administration markedly increased systemic exposure of PB and decreased plasma glutamine availability after breakfast in the healthy adults [6] .…”

Section: Introductionmentioning

confidence: 99%

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

Nakajima

Osaka

Mizuno

et al. 2021

Molecular Genetics and Metabolism Reports

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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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Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis

Cited by 9 publications

References 32 publications

Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults

Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults

Proposal of a liver histology‐based scoring system for bile salt export pump deficiency

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

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