Associations of CYP2C9 and CYP2C19 Pharmacogenetic Variation with Phenytoin‐Induced Cutaneous Adverse Drug Reactions

Abstract

The role of cytochrome P450 (CYP)2C9 and CYP2C19 genetic variation in risk for phenytoin‐induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B (HLA‐B)*15:02 risk allele. In the multi‐ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self‐identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non‐Hispanic. We identified 264 (69%) CYP2C9*1/*1, 77 (20%) CYP2C9*1/*2, and 29 (8%) CYP2C9*1/*3. We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin‐induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared with CYP2C9*1/*1 participants (odds ratio 4.47; 95% confidence interval 1.64–11.69; P < 0.01). Among participants with low‐intermediate and poor CYP2C9 metabolizer genotypes, eight (22%) who also had extensive and rapid CYP2C19 metabolizer genotypes experienced cutaneous adverse events, compared with none of those who also had intermediate CYP2C19 metabolizer genotypes (P = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin‐induced cutaneous adverse events in the absence of the HLA‐B*15:02 risk allele.

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

“…The CYP2C9 nonsynonymous variants with abnormal catalytic activity have been associated with altered metabolism of many drug substrates including warfarin 99 . Patients with low enzyme activity are at risk of CYP2C9 substrate‐related ADRs 100–102 …”

“…99 Patients with low enzyme activity are at risk of CYP2C9 substrate-related ADRs. [100][101][102] Although CYP2C9 plays a minor role in the metabolism of ketamine, in vitro studies showed differential catalytic activity of CYP2C9 variants on ketamine metabolism. 97 Zheng et al evaluated the catalytic activity of 38 CYP2C9 alleles on ketamine metabolism in vitro.…”

Risk-conferringHLAvariants in an epilepsy cohort: benefits of multifaceted use of whole genome sequencing in clinical practice

“…The proxy polymorphisms rs10484555 and rs1061235 were used to confirm the presence of HLA-B*15:02 and HLA-A*31:01 respectively [24,25] and were examined in the Integrative Genomics Viewer (IGV) tool [26]. We selected further genes and single nucleotide polymorphisms reported to be associated with drug and/or metabolite level or maintenance dosing of aromatic ASMs [27][28][29][30]…”

Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

“…The carriers of allelic variants of CYP2B6 T983C were in 4.2-fold higher risk to develop SJS/TEN due to low clearance of nevirapine ( Ciccacci et al, 2013 ). Studies showed the variation in drug clearance enzyme CYP2C9*3 contributed to phenytoin-related SCARs with reduced drug clearance rate ( Chung et al, 2014 ; Tassaneeyakul et al, 2016 ; Wu et al, 2018 ; Su et al, 2019 ; Sukasem et al, 2020b ; Fohner et al, 2020 ), independently of HLA-B*15:02 risk allele. Glutathione-S-transferases (GST), which is a family of metabolic enzyme, plays a crucial role in the drug detoxification and activates some chemicals in a few cases.…”