Relationship of cytochrome P450 gene polymorphisms with blood concentrations of hydroxychloroquine and its metabolites and adverse drug reactions

Abstract

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 concentrations 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 the patients were recorded. The blood concentrations of HCQ and its metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Genotyping of single nucleotide polymorphisms (SNPs) in CYP450, a metabolic enzyme involved in the HCQ metabolic pathway, was performed using a MassARRAY system. The chi-square test, T-test, and one-way analysis of variance were used to analyse data.

Results: Among 29 candidate SNPs, we found that CYP3A4 (rs3735451) was significantly associated with blood levels of HCQ and its metabolites in both the unadjusted model and adjusted model (patients taking HCQ for > 10 years) (P < 0.05). For CYP3A5 (rs776746), a greater risk of skin and mucous membrane ADRs was associated with the TT genotype than with the CT + CC genotypes (P = 0.033). For CYP2C8 (rs1058932), the AG genotype carried a greater risk of abnormal renal function than the AA + GG genotype (P = 0.017); for rs10882526, the GG genotype carried a greater risk of ophthalmic ADRs than 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 optimise HCQ administration and predict ADRs.

Keywords: Adverse drug reactions; Blood concentration; CYP450 gene polymorphism; Hydroxychloroquine; Rheumatoid arthritis; Systemic lupus erythematosus.

Fig. 1

Correlation between the daily dose groups and concentrations of HCQ and its metabolites. a Concentration of hydroxychloroquine (HCQ); b concentration of desethyl hydroxychloroquine (DHCQ); c concentration of desethyl chloroquine (DCQ); d concentration of bisdesethyl chloroquine (BDCQ)

Fig. 2

Time-course of blood concentrations of HCQ and its metabolites in SLE and RA patients receiving 100, 200, 300 or 400 mg HCQ daily. a HCQ; b DHCQ; c DCQ; and d BDCQ (n = 6, n = 74, n = 46 and n = 20 for 100, 200, 300 and 400 mg dose groups, respectively.)

Fig. 3

The distribution of HCQ blood concentration in different genotype groups in the adjusted model. a The distribution of HCQ in different genotype groups. The CC genotype group showed significantly higher concentration than the CT genotype group (P < 0.05), but no significant difference in the CT, TT genotype groups (P > 0.05). b The distribution of DHCQ in different genotype groups. There was no significant difference in the CC, CT and TT genotype groups (P > 0.05). c The distribution of DCQ in different genotype groups. The CC genotype group showed significantly higher concentrations than the CT genotype group (P < 0.05), but there was no significant difference in the CT and TT genotype groups (P > 0.05). d The distribution of BDCQ in different genotype groups. The CC genotype group showed significantly higher concentrations than the CT genotype groups (P < 0.05), but there was no significant difference in the CT and TT genotype groups (P > 0.05)