The Experts for Comprehensive, Convenient Personalized Health!
The Experts for Comprehensive, Convenient Personalized Health!
CYP2C9
The CYP2C9 enzyme composes roughly 20% of hepatic CYP450 content and accounts for the highest level of enzyme expression among the CYP2C family (Ingelman-Sundberg, et al. 2007). Approximately 10% of drugs are metabolized by CYP2C9, including a number of clinically important drugs, such as the antidiabetic drugs tolbutamide and glipizide, the anticonvulsants phenytoin and fosphenytoin, warfarin, losartan, torsemide, and a number of non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, celecoxib, diclofenac, meloxicam, and piroxicam (Lee, 2013; Sangkuhl, 2021). The CYP2C9 gene is known to be highly polymorphic, with over 61 identified variant allele and numerous suballeles (Theken, et al. 2020).
CYP2C9 and Phenytoin
Approximately 80% of phenytoin is eliminated via hepatic oxidative metabolism, which involves the formation of an isomeric mixture of 5-(-4-hydroyphenyl)-5-phenyhydantion (HPPH) metabolites via 4-hydroxylation (Miners, 1998; Giancarlo 2001). The most common isomer (S)-HPPH, is formed via CYP2C9-mediated metabolism, whereas (R)-HPPH is produced in much smaller quantities by the CYP2C19 enzyme. Because phenytoin is associated with a narrow therapeutic window, elevated serum drug levels resulting from minor alterations in CYP2C9 enzyme activity can lead to concentration related toxicities affecting nervous system function (Ninomiya, 2000; Kidd, 1999). The mean maintenance phenytoin dose required for individuals with a least one CYP2C9mutant allele (*2 or *3) is approximately 30% lower than the dose for individuals homozygous for CYP2C9*1 (van der Weide, et al. 2001). However, the CYP2C9*3allele appears to have the greatest effect on warfarin metabolism with studies demonstrating a 3-fold increase in associated drug half-life and a 4-fold increase in AUC (area under the plasma concentration vs. time curves) for individuals homozygous for the *3 allele (CYP2C9*3/*3) compared to those with a CYP2C9*1/*1 genotype (Lee, 2013; Kidd, 1999).
HLA-B and HLA-A encode cell surface proteins that present immune cells with intracellular antigens or peptides produced in the normal breakdown of cellular proteins (Phillips, et al. 2018). Under normal physiological conditions, presented antigens are recognized as “self”; however, antigens derived from pathogens and transplanted tissues can be identified as “non-self” and activate a subsequent immune response. assist in recognition of foreign molecules and pathogens (Martin, et al. 2012). Specific HLA-B and HLA-A gene variants are shown to be associated with immunologically mediated severe cutaneous adverse drug reactions (SCAR), including Steven-Johnson Syndrome (SJS), toxic epidermal necrosis (TEN), and drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) (Chung, et al. 2016). Although the prevalence of SCAR is low (occurring at a rate of approximately 2%), associated mortality rates can be as high as 50% (SJS, 5-10%; SJS-TEN overlap, 30%; TEN, 50%, and DIHS, 10%). Allele variants of interested with published CPIC guidelines include: HLA-B*57:01, HLA-B*58:01, HLA-B*15:02, and HLA-A*31:01(Hershfield, 2013; Phillips, 2018; Martin, 2012; Karnes, 2021).
The HLA-B*15:02variant allele is shown to cause an increased risk of developing SJS/TEN with certain aromatic anticonvulsants, which most commonly occurs withing 4 to 28 days of therapy (Phillips, 2018; Karnes, 2021). Similar to other HLA variants, HLA-B:15:02is expressed in a codominant pattern with genotyping results reported as either positive (1-2 copies) or negative (0 copies). While this risk is thought to be associated with all aromatic anticonvulsants, evidence may be limited or lacking for eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital and appears to be strongest for carbamazepine and oxcarbazepine. Prevalence of HLA-B*15:02is highest in East Asian and Central/South Asian populations (1% to > 20%), followed by European populations (0-1%), and is absent in several sub-Saharan African populations. Updated phenytoin prescription labeling now includes a cautionary statement noting limited evidence suggesting HLA-B*1502 as a risk factor for SJS/TEN in patients of Asian ancestry (Dilantin_PI, 2022). In contrast, carbamazepine labeling has added a black box warning regarding HLA-B*1502 and SJS/TENS, noting a 10-fold higher risk among patients of Asian ancestry and recommends screening such individuals prior to initiating treatment with carbamazepine (Tegretol_2020). Similarly, oxcarbazepine prescription labeling include a black box warning recommending HLA-B*15:02 genotyping as a screening tool in genetically at-risk populations including those of Asian ancestry (Trileptal_PI, 2021).
In contrast to HLA-B*15:02, the HLA-A*31:01 variant allele is shown to cause a broader spectrum of HSR, including maculopapular exanthema (MPE), DRESS, and SJS/TEN in several different ancestral populations (Phillips, et al. 2018). Evidence supporting the association between HSRs and the presence of HLA-A*31:01 is strongest for DRESS and SJS/TEN in populations of European and Japanese ancestry which have high frequencies of carrier status. As a codominant allele, HLA-A*31:01genotyping is express as either positive (1-2 copies) or negative (0 copies). Although cautionary statements regarding HLA-A*31:01 and the associated risk HSR is included in labeling for both carbamazepine and oxcarbazepine, current evidence appears to be lacking with regard to oxcarbazepine.