Background: Hydroxychloroquine (HCQ) is a cornerstone therapy for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study aimed to investigate the relationship of cytochrome P450 (CYP450) gene polymorphisms with blood concentration of HCQ and its metabolites and adverse drug reactions (ADRs) in patients with SLE and RA.
Methods: A cohort of 146 patients with SLE and RA treated with HCQ was reviewed. The ADRs of patients were recorded. The blood concentration of HCQ and its metabolites were measured by liquid chromatography–mass spectrometry analysis. Genotyping of single nucleotide polymorphism (SNP) in CYP450 metabolic enzyme involved in HCQ metabolic pathway was performed using a MassARRAY system. Chi-square test, T-test, and one-way analysis of variance were used to analyze data.
Results: Among 29 candidate SNPs, we found that CYP3A4 (rs3735451) was significantly associated with blood levels of HCQ and its metabolites in unadjusted model and adjusted model (patients taking HCQ for >10 years) (P<0.05). For CYP3A5 (rs776746), skin and mucous membrane ADRs associated with the TT genotype were a greater risk than for the CT+CC genotypes (P=0.033). For CYP2C8 (rs1058932), abnormal renal function with the AG genotype carried a greater risk than with the AA+GG genotype (P=0.017); for rs10882526, ophthalmic ADRs of the GG genotype carried a greater risk than for the AA+AG genotypes (P=0.026).
Conclusions: The CYP2C8 (rs1058932 and rs10882526) and CYP3A5 (rs776746) polymorphisms are likely involved in the ADRs of HCQ. Gene polymorphism analysis of CYP450 and therapeutic drug monitoring of HCQ and its metabolites might be useful to optimize HCQ administration and predict ADRs.