title: Association of Polymorphisms of Cytochrome P450 2D6 With Blood Hydroxychloroquine Levels in Patients With Systemic Lupus Erythematosus.
abstract: OBJECTIVE
  To evaluate associations of genetic polymorphisms in cytochrome P450 (CYP) isoforms 2D6, 3A5, and 3A4 with blood concentrations of hydroxychloroquine (HCQ) and its metabolite, N-desethyl HCQ (DHCQ), in patients with systemic lupus erythematosus (SLE).
  
  
  METHODS
  SLE patients taking HCQ for >3 months were recruited and were genotyped for 4 single-nucleotide polymorphisms in CYP2D6*10, CYP3A5*3, and CYP3A4*18B. Blood HCQ and DHCQ concentrations ([HCQ] and [DHCQ]) were measured and their association with corresponding genotypes was investigated.
  
  
  RESULTS
  A total of 194 patients were included in the analysis. CYP2D6*10 polymorphisms (rs1065852 and rs1135840) were significantly associated with the [DHCQ]:[HCQ] ratio after adjustment for age, sex, dose per weight per day, and SLE Disease Activity Index score (P = 0.03 and P < 0.01, respectively). In adjusted models, the [DHCQ]:[HCQ] ratio was highest in patients with the G/G genotype of the CYP2D6*10 (rs1065852) polymorphism and lowest in those with the A/A genotype (P = 0.03). Similarly, the [DHCQ]:[HCQ] ratio was highest in patients with the C/C genotype of the CYP2D6*10 (rs1135840) polymorphism and lowest in those with the G/G genotype (P < 0.01). The CYP2D6*10 (rs1065852) polymorphism was significantly related to the [DHCQ] (P = 0.01). However, the polymorphisms of CYP3A5*3 and CYP3A4*18B did not show any significant association with the [HCQ], [DHCQ], or [DHCQ]:[HCQ] ratio.
  
  
  CONCLUSIONS
  Our study showed that the [DHCQ]:[HCQ] ratio was related to CYP2D6 polymorphisms in Korean lupus patients taking oral HCQ. CYP polymorphisms may explain why there is wide variation in blood HCQ concentrations. The role of an individual's CYP polymorphisms should be considered when prescribing oral HCQ.
authors: Catholic University of Korea and Seoul St. Mary's Hospital, Seoul, Republic of Korea.
authors: Ji Yeon
authors: JY
authors: Lee
authors: Catholic University of Korea, Seoul, Republic of Korea.
authors: Nadimuthu
authors: N
authors: Vinayagamoorthy
authors: Catholic University of Korea, Seoul, Republic of Korea.
authors: Kyungdo
authors: K
authors: Han
authors: Catholic University of Korea and Seoul St. Mary's Hospital, Seoul, Republic of Korea.
authors: Seung Ki
authors: SK
authors: Kwok
authors: Catholic University of Korea and Seoul St. Mary's Hospital, Seoul, Republic of Korea.
authors: Ji Hyeon
authors: JH
authors: Ju
authors: Catholic University of Korea and Seoul St. Mary's Hospital, Seoul, Republic of Korea.
authors: Kyung Su
authors: KS
authors: Park
authors: Catholic University of Korea, Seoul, Republic of Korea.
authors: Seung-Hyun
authors: SH
authors: Jung
authors: Catholic University of Korea, Seoul, Republic of Korea.
authors: Sung-Won
authors: SW
authors: Park
authors: Catholic University of Korea, Seoul, Republic of Korea.
authors: Yeun-Jun
authors: YJ
authors: Chung
authors: Catholic University of Korea and Seoul St. Mary's Hospital, Seoul, Republic of Korea.
authors: Sung-Hwan
authors: SH
authors: Park
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000097:blood* / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006801:Humans; D006886:Hydroxychloroquine / Q000031:analogs & derivatives* / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy*; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
chemical_list: D018501:Antirheumatic Agents; D006886:Hydroxychloroquine; C049283:cletoquine; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human