An update on CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects

ABSTRACT

Introduction

Phenytoin is a frequently used drug treatment for epilepsy. Genetic polymorphisms in the metabolism of phenytoin, particularly CYP2C9, are strongly associated with increased plasma concentrations and can result in toxicity. Human leukocyte antigen (HLA) alleles are well-known genetic predictors of certain antiepileptic drug-associated severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recent pharmacogenomic studies show genetic polymorphisms in CYP2C9, as well as HLA alleles, are significantly associated with phenytoin-related SCAR.

Areas covered

Updated pharmacogenomic information of CYP2C9 variants and HLA alleles involved in phenytoin-associated cutaneous adverse drug reactions (cADRs) are discussed in this article.

Expert opinion

CYP2C9*3

has been identified as the most significant genetic variant associated with increased phenytoin concentrations and adverse events. Recent pharmacogenomic findings reveal that CYP2C9*3 and HLA alleles, i.e. HLA-B*15:02, HLA-B*13:01, and HLA-B*51:01, are important genetic variants in the occurrence of phenytoin-induced cADRs or SCAR. A phenotype- and population-specific multigene panel can be used before prescribing to predict phenytoin-induced cADRs and further guide optimal dose selection.

KEYWORDS:

• Adverse drug reaction (ADR)
• CYP2C9
• human leukocyte antigen (HLA)
• pharmacogenomics
• phenytoin
• Stevens-Johnson syndrome (SJS)
• toxic epidermal necrolysis (TEN)

Article highlights

• Cytochrome P450 enzymes, particularly CYP2C9 and CYP2C19, are major enzymes in the metabolism and elimination of phenytoin. CYP2C9*3 variant is the most significantly associated with increased phenytoin plasma concentrations and more frequent adverse drug reactions (ADRs).

• Patients carrying CYP2C9*3 allele are more likely to develop phenytoin-induced SCAR, including SJS and TEN, compared with those with wild-type (CYP2C9*1) allele.

• In addition to CYP2C9*3, HLA-B*15:02, HLA-B*13:01 and HLA-B*51:01 are significantly associated with phenytoin-induced SCAR, as well as other cutaneous ADRs, particularly in patients of Asian ancestries.

• Combining the assessment of CYP2C9*3 and high-risk HLA alleles can better identify individuals at risk of phenytoin-induced cADRs and improve the safety and effectiveness of phenytoin use.

This box summarizes key points contained in the article.

Acknowledgments

WH Chung receives funding from the Ministry of Science and Technology, Taiwan (MOST103-2321-B-182A-006; MOST101-2628-B-182A-001-MY3; MOST104-2314-B-182A-148-MY3; MOST105-2325-B-182A-006; MOST106-2622-B-182A-003-CC2; MOST107-2622-B-182A-003-CC2; MOST106-2314-B-182A-037-MY3) and the Chang Gung Memorial Hospital (CLRPG2E0051~3; CLRPG3J0011~2; CMRPG3D0351~3; CMRPG3D0361~3; CORPG3F0041~3; CIRPG3I0041~2; CIRPG3I0021~2).

Declaration of interest

B Carleton has a Canadian federal agency grant from Genome Canada (Genomic Applications Partnership Program). This grant requires matching funds from an industry partner.  Funds were provided from Dynacare Next specialized diagnostics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.