Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms

Abstract

Pharmacogenetic studies have shown that genetic defects in drug-metabolizing enzymes encoded by CYP2C9, CYP2C19 genes and by the transporter ABCB1 gene can influence phenytoin (PTH) plasma levels and toxicity. The patient reported here is a 2-year-old girl with a medical history of cryptogenic (probably symptomatic) epilepsy, who had her first focal seizure with secondary generalization at 13 months of age. She initially received oral valproate treatment and three months later, she was prescribed an oral oxcarbazepine treatment. At 20 months of age, she was admitted to the Emergency Department because of generalized convulsive Status Epilepticus needing to be immediately treated with rectal diazepam (0.5 mg kg(-1)), intravenous diazepam (0.3 mg kg(-1)), and intravenous phenytoin with an initial-loading dose of 15 mg kg(-1). However, two hours after the initial-loading dose of PTH, the patient developed dizziness, nystagmus, ataxia and excessive sedation. Other potential causes of PTH toxicity were excluded such as drug interactions, decreased albumin or lab error. Therefore, to explain the neurological toxicity, PTH plasma levels and CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms were analyzed. Initial plasma PTH levels were higher than expected (69 mg l(-1); normal range: 10-20 mg l(-1)), and the patient was homozygous for the CYP2C9*2 allele, heterozygous for the CYP2C19*4 allele and homozygous for the 3435C and 1236C ABCB1 alleles. Present findings support the previously established relationship between CYP2C9 and CYP2C19 genetic polymorphisms and the increased risk to develop PTH toxicity owing to high plasma concentrations. Nevertheless, although the association of these genes with PTH-induced adverse effects has been well-documented in adult populations, this is the first report examining the influence of these genetic polymorphisms on PTH plasma levels and toxicity in a pediatric patient.

CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy

“…25,55 In this study, we did not observe a significant difference on PHT plasma concentrations among patients' carriers of different ABCB1 genotypes and haplotypes. It has been reported that the discrepancy in the association studies of ABCB1 polymorphisms in epilepsy treatment could be due to confounders such as ethnicity and polytherapy.…”

“…23 Several pharmacogenetic studies have shown the influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms on PHT plasma concentrations and its association with PHT-induced central nervous system toxicities. [24][25][26] However, the influence of CYP2C9 IVS8-109 A4T and CYP2C19*17 variants on PHT plasma concentrations has not been explored. The aim of this study was to assess the potential influence of CYP2C9 (*2, *3 and IVS8-109 A4T), CYP2C19 (*2, *3 and *17) and ABCB1 (1236C4T, 2677G4 A/T and 3435C4T) polymorphisms and concomitant treatment on PHT plasma concentrations in Mexican Mestizo (MM) patients with epilepsy.…”

Independent Predictors of Delay in Emergence From General Anesthesia

“…31,32 In epilepsy patients with genetic polymorphisms in CYP2C9 and CYP2C19, excessive sedation was observed as a clear clinical symptom of a higher plasma phenytoin level. 33 In our previous report, valproic acid was related to a decrease in propofol dose for sedation. 25 Thus, an enhancing sedative effect of anesthetics may be common among AEDs with side effects of sedation/fatigue/tiredness.…”

Associations between HLA class I and cytochrome P450 2C9 genetic polymorphisms and phenytoin-related severe cutaneous adverse reactions in a Thai population

“…This variant allele results from an A1075C mutation on exon 7 causing an amino acid at position 359 to change from isoleucine to leucine, which results in an almost 90-95% reduction in phenytoin clearance compared with that of the wild-type enzyme [31,34]. Patients with homozygous CYP2C9 variant alleles or CYP2C9 poor metabolizers appear to be at a higher risk for the dose-related toxicities of phenytoin than patients homozygous for the wild-type allele or CYP2C9 extensive metabolizers [35,36]. In addition, the risk of cutaneous adverse reactions of phenytoin, which, in the past, were known as idiosyncratic reactions that are not related to the dose, was reported to be increased about 170-fold in the Korean patients who carried the CYP2C9*3 variant [37].…”