title: The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients.
abstract: Pulsed low-dose cyclophosphamide (CTX) therapy has become a very effective approach in improving the clinical outcomes of lupus nephritis (LN) patients. However, variations of CTX therapeutic outcomes in LN patients are incompletely understood. We investigated the contributions of known allelic variants to CTX therapy outcomes in 77 LN patients. Then, 22 out of the 77 patients were randomly enrolled to evaluate the pharmacokinetic profiles. LN patients with a GSTA1*A mutation (CT heterozygous) had more risk of non-remission (44% vs. 20%, P=0.005). Pharmacokinetic data indicated that patients with a GSTA1*A heterozygous variant had a lower exposure to 4-hydroxycyclophosphamide (4OHCTX) compared to wild-type patients (AUC4OHCTX: 12.8 (9.8, 19.5) vs. 27.5 (18.1, 32.8) h mg/l, P=0.023). Clinical remission was significantly related to higher exposure of 4OHCTX (P=0.038). In conclusion, LN patients with GSTA1*A heterozygous genotypes had poor CTX treatment remission due to less exposure to activated metabolites of CTX.
authors.affiliation: Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Hong-Na
authors.initials: HN
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Xiao-Ye
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Qiong-Hong
authors.initials: QH
authors.lastname: Xie
authors.affiliation: Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Lin-Yun
authors.initials: LY
authors.lastname: Lai
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Yuan-Cheng
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China. Electronic address: xuejun@fudan.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Chuan-Ming
authors.initials: CM
authors.lastname: Hao
authors.affiliation: Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Shan-Yan
authors.initials: SY
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; C484555:GSTA1 protein, human; D005982:Glutathione Transferase
keywords: Cyclophosphamide; GSTA1; Lupus nephritis; Pharmacogenomics; Pharmacokinetics