RESUMO
Objective:To investigate factors associated with the concentration of hydroxychloroquine (HCQ) and its metabolites in peripheral blood of patients with systemic lupus erythematosus (SLE) who were receiving long-term oral HCQ treatment.Methods:SLE patients who had been taking HCQ for more than 3 months were recruited. Clinical characteristics, laboratory test results and SLE disease activity index (SLEDAI) scores were examined. The concentrations of HCQ and its metabolites from peripheral blood were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Student's-test and Nonpara-metric tests were used to compare quantitative data, Chi-square and Fisher's exact tests were used to analyze qualitative data. Correlation between the test results was assessed by correlation coefficient. Variables with P values less than 0.05 in univariate analysis were entered into a logistic regression model. Results:In total, 191 SLE patients on long-term HCQ treatment were included in the analysis. Medians of HCQ blood concentrations ([HCQ]), desethylhydroxychloroquine (DHCQ) blood concentrations ([DHCQ]), desethylchloroquine (DCQ) blood concentrations ([DCQ]) and bisdesethylchloroquine (BDCQ) blood concentrations ([BDCQ]) were 523.19 (402.63, 677.88) ng/ml, 291.79 (212.30, 432.51) ng/ml, 49.37 (35.00, 73.05) ng/ml, 21.78(14.37, 52.46) ng/ml respectively. On multivariate analysis, weight-adjusted oral HCQ dose [ OR(95% CI)=1.366 (1.053, 1.772) , P=0.019], the course of hydroxychloroquine [ OR (95% CI) =0.991 (0.984, 0.999), P=0.026], estimated glomerular filtration rate [ OR(95% CI)=0.984 (0.971, 0.997), P=0.014] and platelet count [ OR (95% CI)=1.010 (1.005, 1.015), P<0.001] were associated with [HCQ]. [HCQ], [DCQ], [BDCQ], [BDCQ]/[HCQ] were negatively correlated with estimated glomerular filtration rate (eGFR) ( r=-0.20, P=0.006; r=-0.19, P=0.010; r=-0.26, P<0.001; r=-0.15, P=0.044, respectively) after adjusted for age, course of disease, duration of HCQ treatment and weight adjusted HCQ dosage, [DHCQ]/[HCQ] was negatively correlated with the SLEDAI score ( r=-0.16, P=0.027) when the effects of glucocorticoid was controlled, [BDCQ]/[HCQ] among different renal function levels was statistically significant ( H=12.46, P=0.014). Conclusion:The factors associated with HCQ blood concentrations in SLE patients on long-term oral HCQ treatment are weight-adjusted HCQ dosage, duration of hydroxychloroquine intake and renal function. In addition, [BDCQ] is closely correlated with renal function, [DHCQ] is correlated with SLE disease activity.
RESUMO
OBJECTIVE： To study the relationship of CYP3A4， CYP2C8 and CYP3A5 gene polymorphism with ADR/blood concentration of hydroxychloroquine in patients with autoimmune disease （AID）， and to provide reference for individual medication of hydroxychloroquine. METHODS： Totally 77 AID patients，who were treated with hydroxychloroquine （daily dose of 200 mg to 400 mg） for a long-term （＞6 months）， were selected from the department of rheumatology and immunology， the First Affiliated Hospital of Anhui Medical University during Jul. 2017 to Aug. 2018. The information， blood sample and ADR of them were collected. Those patients were divided into normal liver function group， abnormal liver function group， normal renal function group， abnormal renal function group， normal eye group and abnormal eye group according to the site of ADR. The concentration of hydroxychloroquine was determined by HPLC. Genotype of CYP3A4， CYP2C8 and CYP3A5 were detected by MassARRAY microarray system. The differences of hydroxychloroquine-induced ADR in different genotypes were analyzed by χ2 test. The blood concentration difference of hydroxychloroquine in different genotypes were analyzed by independent sample t-test and one-way ANOVA. RESULTS： There was statistical significance in the distribution of CYP3A5 rs4646453 locus between normal renal function group and abnormal renal function group（P＜0.05）. The incidence of CC genotype was higher than that of AA+AC genotype in abnormal renal function group. There was statistical significance in the distribution of CYP2C8 rs10882526 locus between normal liver function group and abnormal liver function group（P＜0.05）. The incidence of allele G was higher than that of allele A in abnormal liver function group， and the incidence of AG genotype was higher than that of AA genotype. There was no significant correlation of the gene polymorphisms of CYP3A4， CYP2C8 and CYP3A5 with blood concentration among 77 AID patients. In subgroup analysis， blood concentration of GT， GG and TT genotypes of CYP2C8 rs10882521 in 58 patients with systemic lupus erythematosus （SLE） were 514.1，735.3 and 785.9 ng/mL， respectively； GG and TT genotypes were significantly higher than GT genotype （P＜0.05）. CONCLUSIONS： AID patients with CYP3A5 rs4646453 CC genotype have a higher incidence of renal dysfunction due to taking hydroxychloroquine； patients with CYP2C8 rs10882526 locus allele G and AG have a relatively high incidence of renal dysfunction due to taking hydroxychloroquine. When SLE patients taking the same dose of hydroxychloroquine， the blood concentration of hydroxychloroquine in patients carrying CYP2C8 rs10882521 GT genotype is lower than other genotypes.