Influence of Acylpeptide Hydrolase Polymorphisms on Valproic Acid Level in Chinese Epilepsy Patients

Wen, Zhi Peng; Fan, Shuang Shi; Du, Can; Yin, Tongming; Zhou, Bo; Peng, Ze Feng; Xie, Yuan Yang; Zhang, Wei; Yao, Chen; Tang, Jie; Xiao, Jian; Chen, Xiao Ping

doi:10.2217/pgs-2016-0030

Cited by 13 publications

(9 citation statements)

References 37 publications

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“…Carbapenem antibiotics can inhibit APEH activity in an irreversible manner, which leads to an increase in urinary excretion of VPA‐G and eventually makes the decreases of VPA plasma concentration . Our previous study have also indicated that concomitant use of MEPM resulted in an increase in urinary excretion of VPA‐G in Chinese epilepsy patients . Additionally, Suzuki's study suggests that the APEH activity could be repressed by more than 90% with only 20 μ mol/L of MEPM in vitro , this nearly complete suppression of APEH can partly explain why the magnitude of VPA plasma concentration decrease is independent of VPA and MEPM daily dose.…”

Section: Discussionsupporting

confidence: 93%

Drug-drug interaction between valproic acid and meropenem: a retrospective analysis of electronic medical records from neurosurgery inpatients

Wen

Fan

et al. 2017

J Clin Pharm Ther

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This is the first study using a large number of VPA TDM records to investigate the change in VPA levels caused by concomitant use of MEPM. Our results imply that the decrease in drug concentration cannot be reversed by increasing VPA dose. Moreover, MEPM daily dose did not influence the drop in VPA plasma level. At least 7 days are required for the recovery of VPA plasma concentration after discontinuation of MEPM.

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Section: Discussionsupporting

confidence: 93%

Drug-drug interaction between valproic acid and meropenem: a retrospective analysis of electronic medical records from neurosurgery inpatients

Wen

Fan

et al. 2017

J Clin Pharm Ther

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“…However, in the present study, neither of these polymorphisms was associated with the VPA C 0 /D ratio in children with epilepsy who received VPA monotherapy. In fact, the aforementioned studies did not mention dosage forms (11,30,32) or perform a separate analysis of those data (11,12). In our study, the age-related C 0 /D ratio was significantly associated with UGT2B7 G211T, and T802C polymorphisms in patients who were administered VPA oral solutions, rather than VPA SR tablets, along with other antiepileptic drugs (data not shown).…”

Section: Discussionmentioning

confidence: 55%

Genetic and Non-genetic Factors Contributing to the Significant Variation in the Plasma Trough Concentration-to-Dose Ratio of Valproic Acid in Children With Epilepsy

Guo

et al. 2021

Front. Pediatr.

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Objective: This study was conducted to evaluate the potential genetic and non-genetic factors contributing to plasma trough concentration-to-dose (C0/D) ratio of valproic acid (VPA) in pediatric patients with epilepsy.Study Design: A single-center, retrospective cohort study was performed by collecting data from 194 children aged 1–14 years between May 2018 and November 2018. The oral solution (n = 135) group and the sustained-release (SR) tablet group (n = 59) were defined, and the plasma VPA C0 was measured. Twenty-six single-nucleotide polymorphisms (SNPs) were chosen for genotyping with the MassARRAY system. A multiple logistic regression model was used for data analysis.Results: Body weight (BW) and age were positively correlated with the C0/D ratio in 194 patients, but the positive correlation disappeared after the patients were divided into oral solution and SR tablet subgroups. The average C0/D ratio was significantly increased by 2.11-fold (P = 0.000) in children who took VPA SR tablets compared with children who were administered VPA oral solutions. No significant association between genetic variants and the C0/D ratio was found, even for the five well-studied SNPs, namely UGT2B7 G211T, C802T, C161T, T125C, and CYP2C9*3 A1075C. However, a significant association between the C0/D ratio and UGT1A6/9 Del>A (rs144486213) was observed in the VPA oral solution group, but not in the VPA SR tablet group.Conclusions: The dosage forms of sodium valproate, rather than BW, age, or genetic polymorphisms, significantly affected the VPA C0/D ratios in pediatric patients with epilepsy. Based on our findings, switching the dosage form between solution and SR tablet should be performed cautiously. Total daily dose adjustment should be considered, and the plasma concentration, seizure-control effect, and adverse drug reaction should also be monitored very closely.

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“…The study of VPA-d6 β-D-glucuronide (VPA-G) concentration in APEH rs3816877 and rs1131095 carriers revealed that patients with the APEH rs3816877 C/C genotype show higher levels than C/T carriers in the Chinese population [283]. Valproate-related neuroprotection in experimentally triggered epileptic seizures has been associated with PKC-dependent GABAAR γ2 phosphorylation at serine 327 residue [284]. SOD2 Val16Ala polymorphism may affect γ-glutamyltransferase (GGT) elevation in epileptic patients treated with VPA [285].…”

Section: Epilepsymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

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Influence of Acylpeptide Hydrolase Polymorphisms on Valproic Acid Level in Chinese Epilepsy Patients

Abstract: APEH polymorphism has significant influence on VPA pharmacokinetics in Chinese population.

Cited by 13 publications

References 37 publications

Drug-drug interaction between valproic acid and meropenem: a retrospective analysis of electronic medical records from neurosurgery inpatients

Drug-drug interaction between valproic acid and meropenem: a retrospective analysis of electronic medical records from neurosurgery inpatients

Genetic and Non-genetic Factors Contributing to the Significant Variation in the Plasma Trough Concentration-to-Dose Ratio of Valproic Acid in Children With Epilepsy

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

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