The influence of UGT2B7 genotype on valproic acid pharmacokinetics in Chinese epilepsy patients

Sun, Yi‐Min; Zhuo, Wen-Yan; Lin, Hong; Peng, Zhengke; Wang, Huaming; Huang, H.S.Y.; Luo, Yan; Tang, Faqing

doi:10.1016/j.eplepsyres.2015.04.015

Cited by 39 publications

(25 citation statements)

References 13 publications

(14 reference statements)

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“…The results show that A268G and C802T polymorphisms exert influences on the metabolism of VPA, which is consistent with previous research [25,26]. Further analysis on efficacy indicated that C802T polymorphism could affect the efficacy of VPA.…”

Section: Discussionsupporting

confidence: 92%

“…Ma et al reported that UGT2B7 A268G polymorphism was involved in the metabolism of VPA and affects serum concentration of VPA [25]. Xiang et al analyzed C802T and G211T polymorphisms in epilepsy patients and concluded that C802T is an important determinant of individual variability in the pharmacokinetics of VPA, while G211T had no influence on the serum concentration of VPA [26]. …”

Section: Discussionmentioning

confidence: 99%

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Association of UGT2B7 and UGT1A4 Polymorphisms with Serum Concentration of Antiepileptic Drugs in Children

Jiao

Shi

2016

Med Sci Monit

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BackgroundThis study aimed to analyze the relationship of UGT2B7 and UGT1A4 polymorphisms with metabolism of valproic acid (VPA) and lamotrigine (LTG) in epileptic children.Material/MethodsWe administered VPA (102) and LTG (102) to 204 children with epilepsy. Blood samples were collected before the morning dose. Serum concentration of LTG was measured by high-performance liquid chromatography (HPLC). Serum VPA concentration was tested by fluorescence polarization immunoassay. UGT2B7 A268G, C802T, and G211T polymorphisms, as well as UGT1A4 L48V polymorphism, were assayed by direct automated DNA sequencing after PCR. Evaluation of efficacy was conducted using the Engel method.ResultsThe adjusted serum concentration of VPA was 4.26 μg/mL per mg/kg and LTG was 1.56 μg/mL per mg/kg. Multiple linear regression analysis revealed that VPA or LTG adjusted concentration showed a good linear relation with sex and age. UGT2B7 A268G and C802T polymorphisms were demonstrated to affect the serum concentration of VPA (F=3.147, P=0.047; F=22.754, P=0.000). UGT1A4 L48V polymorphism was not related with the serum concentration of LTG (F=5.328, P=0.006). In the efficacy analysis, we found that C802T polymorphism exerted strong effects on efficacy of VPA (χ2=9.265, P=0.010). L48V polymorphism also showed effects on efficacy of LTG (χ2=17.397, P=0.001).ConclusionsUGT2B7, UGT1A4 polymorphisms play crucial roles in metabolism of VPA and LTG.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Association of UGT2B7 and UGT1A4 Polymorphisms with Serum Concentration of Antiepileptic Drugs in Children

Jiao

Shi

2016

Med Sci Monit

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“…Using the combination of this value and in vitro inhibition kinetic parameter (Ki) obtained in our recent study, the value of AUC i /AUC was calculated to be 1.17, indicating the highly possible drug–drug interaction between atractylenolide I and drugs mainly undergoing UGT2B7‐catalysed metabolism. UGT2B7 catalysed the metabolism of many important clinical drugs, such as zidovudine (Yuan et al ., ) and valproic acid (Sun et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III

et al. 2015

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Drug-metabolizing enzymes inhibition-based drug-drug interaction remains to be the key limiting factor for the research and development of efficient herbal components to become clinical drugs. The present study aims to determine the inhibition of uridine 5'-diphospho-glucuronosyltransferases (UGTs) isoforms by two important efficient herbal ingredients isolated from Atractylodes macrocephala Koidz, atractylenolide I and III. In vitro recombinant UGTs-catalysed glucuronidation of 4-methylumbelliferone was used to determine the inhibition capability and kinetics of atractylenolide I and III towards UGT2B7, and in silico docking method was employed to explain the possible mechanism. Atractylenolide I and III exhibited specific inhibition towards UGT2B7, with negligible influence towards other UGT isoforms. Atractylenolide I exerted stronger inhibition potential than atractylenolide III towards UGT2B7, which is attributed to the different hydrogen bonds and hydrophobic interactions. Inhibition kinetic analysis was performed for the inhibition of atractylenolide I towards UGT2B7. Inhibition kinetic determination showed that atractylenolide I competitively inhibited UGT2B7, and inhibition kinetic parameter (Ki) was calculated to be 6.4 μM. In combination of the maximum plasma concentration of atractylenolide I after oral administration of 50 mg/kg atractylenolide I, the area under the plasma concentration-time curve ration AUCi /AUC was calculated to be 1.17, indicating the highly possible drug-drug interaction between atractylenolide I and drugs mainly undergoing UGT2B7-catalysed metabolism.

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“…[32][33][34] Enzyme polymorphisms have an impact on valproate serum concentrations. 35,36 This interethnic variability could explain differences in clearance between the development and validation data sets. Another possible explanation might be differences in valproate concentration assay methods.…”

Section: Discussionmentioning

confidence: 99%

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

Tauzin

Tréluyer

Nabbout

et al. 2018

The Journal of Clinical Pharma

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Valproate is an old-generation antiepileptic drug often used in children. The pharmacokinetics of valproate are noteworthy for a large and difficult to predict interindividual variability in measured serum concentrations and for saturable protein binding. A model-based approach to personalize valproate treatment could be relevant in pediatric patients. The aims of this study were to review all published valproate population pharmacokinetic models in children and assess them by external validation to determine their predictive performance. Through simulations with the best model, we evaluated dosing regimen. A validation data set included valproate serum concentrations assayed during routine therapeutic drug monitoring of epileptic children. We applied to our population 11 published pediatric population pharmacokinetic models. For each model, predictive performance was assessed by external validation, using bias and precision calculations as well as goodness-of-fit plots. Dose simulations were conducted with the best predictive model to evaluate dosing regimen. The validation data set contained 178 valproate concentrations ranging from 13.4 to 128 mg/L from 114 patients. The best model exhibited a mean prediction error of 6.6 mg/L and a root mean squared error of 25.1 mg/L, with no model misspecification evidenced by visual predictive check. In our cohort, half the patients had a trough concentration <50 mg/L. Simulations suggested increasing doses, especially for children ࣘ40 kg. External evaluation of published valproate pharmacokinetic models enabled us to identify a suitable model for simulations and Bayesian forecasting. Dosing regimen should be adjusted to weight, with decreasing doses with increasing weight.

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The influence of UGT2B7 genotype on valproic acid pharmacokinetics in Chinese epilepsy patients

Cited by 39 publications

References 13 publications

Association of UGT2B7 and UGT1A4 Polymorphisms with Serum Concentration of Antiepileptic Drugs in Children

Association of UGT2B7 and UGT1A4 Polymorphisms with Serum Concentration of Antiepileptic Drugs in Children

Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

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