CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy

Abstract

Purpose To perform therapeutic drug monitoring (TDM) of total and free plasma valproic acid (VPA) concentrations in pediatric patients with epilepsy and to analyze related factors. Patients and Methods Pediatric epileptic patients treated in 2015–2019 in our hospital were assessed. Total and free plasma VPA concentrations were obtained by UPLC and LC-MS/MS, respectively. Regression analysis was performed to examine the associations of free plasma VPA with total plasma VPA and plasma protein binding rate. The impacts of individual situation, CYP2C9 genotype, and drug combination on VPA concentration were examined. Results Of the 251 patients, 81 had lower total concentrations than effective therapeutic levels; 86 and 31 patients had infections and central nervous system dysplasia, respectively. VPA’s daily doses and free drug concentrations were significantly lower in the CYP2C9 *3/*3 genotype group versus the CYP2C9 *1/*3 and CYP2C9 *1/*1 groups ( P <0.05). Free and total VPA concentrations were linked by Y = 0.0004 X 2 + 0.042 X + 0.3035 (r=0.6981); VPA plasma protein binding rate and free VPA concentration were related by Y = 0.0003 X 2 - 0.0127 X + 0.9777 (r=0.8136). Both total and free VPA concentrations were significantly decreased in patients simultaneously administered phenobarbital, meropenem and biapenem ( P <0.05), with therapeutic failure after meropenem/biapenem co-administration. Conclusion Free VPA amounts have nonlinear relationships with total VPA amounts and plasma protein binding rate in epileptic children. Additionally, CYP2C9 *3/*3 expression affects VPA metabolism. Since phenobarbital affects VPA metabolism, TDM is recommended. Meanwhile, carbapenem-co-administration with VPA should be prohibited.

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

“…However, these drug-gene interactions were marginal and not sufficient to justify their inclusion in official recommendations or drug labeling. In addition, numerous other polymorphisms annotated in the literature 18,63 and in FDA drug labels for valproate 138 , lamotrigine 139 and carbamazepine 140 as potentially relevant to drug metabolism did not show statistically significant…”

Determination of valproic acid and its six metabolites in human serum using LC–MS/MS and application to interaction with carbapenems in epileptic patients

“…Some reports have shown that CBPMs can inhibit the intestinal transporter and kill the enteric bacteria that can supply β‐glucuronidase, blocking the intestinal absorption of VPA (Mori et al, 2007). In addition, CBPMs have been confirmed to increase VPA's shift into erythrocytes and promote valproic glucuronide formation (Šíma et al, 2017; Wu et al, 2021; Yamamura et al, 2000). The other possible assumption involves the inhibition of acylpeptide hydrolase (APEH) activity by CBPMs, which causes a decrease in VPA β‐D‐glucuronide hydrolysis and therefore enhances the urinary elimination of VPA (Suzuki et al, 2016).…”

“…Furthermore, the serum concentrations of VPA metabolites (3‐OH‐VPA, 4‐OH‐VPA, 2‐ene‐VPA, 4‐ene‐VPA, 3‐keto‐VPA, and 2‐PGA) experienced varying degrees of decrease in epilepsy patients with VPA–CBPM comedication. This may be because the pharmacokinetics of VPA are disturbed by CBPMs, resulting in a reduction in total and free VPA concentrations (Wu et al, 2021). The metabolism of VPA involves three major metabolic pathways, namely the CYP pathway, UGT‐mediated pathway, and mitochondrial β‐oxidation.…”

Serum concentrations of valproic acid in people with epilepsy: Clinical implication

“…Our findings must be corroborated with pharmacogenetic studies by genotype, ethnicity, and miscegenation, as shown by Zhao et al (2020), who observed that the allelic variant UGT2B7 802C>T and age influence the concentration levels of VPA and suggested administering the anti-epileptic with caution in young patients who are poor metabolizers. In a recent study by Wu et al (2021) daily VPA doses and free drug concentrations were found to be significantly lower in patients with CYP2C9*3/*3 allelic variants versus CYP2C9*1/*3 groups and CYP2C9 *1/*1 (p<0.05), pharmacogenetic and TDM studies are recommended.…”