Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
Clin Chim Acta. 2012 Apr 11;413(7-8):683-90. doi: 10.1016/j.cca.2011.12.003. Epub 2011 Dec 22.
This study aimed to evaluate the effect of UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A polymorphisms on the pharmacokinetics (PKs) of mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) in healthy Chinese volunteers and in stable renal transplant patients.
The data were extracted from comparative bioavailability studies conducted in 42 healthy individuals and 37 renal transplant patients. A complete PK profile was obtained over 48 h for healthy volunteers and over 12h for the transplant patients. The MPA/MPAG plasma concentrations were measured by HPLC. The genotypes were determined using either the Taqman probe technique or direct sequencing. A multivariate analysis was used to assess the effect of the genotypes (UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A) and other covariates (age, weight, height, calculated creatinine clearance, serum albumin, haemoglobin and drug comedication) on the AUC(4-12) and AUC(0-12) for MPA and MPAG in the healthy volunteers and patients.
In the healthy volunteers, the dose-adjusted geometric means (GM) of the MPA AUC(4-12) in individuals with the SLCO1B3 334T allele were 30.4% lower than those values in the 334G homozygote carriers (P<0.05); in the transplant patients, the steroid dose was associated with a negative effect on the AUC of MPAG (P<0.03) and weight was associated with a negative effect on the AUC for MPA in the healthy volunteers and patients (P<0.03). No other significant effect of genotype or of the other studied variables on AUC(4-12) or AUC(0-12) of MPA/MPAG was found in the healthy volunteers or patients.
The PKs of MPA is affected by the SLCO1B3 polymorphism in healthy Chinese individuals. The absence of an effect of SLCO1B3 polymorphisms in transplant patients may be due to the co-administration of cyclosporine (CsA). Concomitant steroid dose and weight are two important covariates of the AUC of MPA and MPAG, which should be taken into account in clinical use. Further confirmatory in vivo studies are needed.
本研究旨在评估 UGT1A8*2、SLCO1B3 T334G、ABCC2 C-24T 和 ABCG2 C421A 多态性对健康中国志愿者和稳定肾移植患者中美泊酚酸（MPA）及其酚基葡萄糖醛酸（MPAG）药代动力学（PKs）的影响。
数据来自于 42 名健康个体和 37 名肾移植患者进行的比较生物利用度研究。健康志愿者进行了 48 小时的完整 PK 谱检测，移植患者进行了 12 小时的检测。MPA/MPAG 血浆浓度通过 HPLC 测量。采用 Taqman 探针技术或直接测序法确定基因型。多变量分析用于评估基因型（UGT1A8*2、SLCO1B3 T334G、ABCC2 C-24T 和 ABCG2 C421A）和其他协变量（年龄、体重、身高、计算的肌酐清除率、血清白蛋白、血红蛋白和药物合并用药）对健康志愿者和患者中 MPA 和 MPAG 的 AUC（4-12）和 AUC（0-12）的影响。
在健康志愿者中，携带 SLCO1B3 334T 等位基因的个体的 MPA AUC（4-12）剂量调整后的几何平均值（GM）比 334G 纯合子携带者低 30.4%（P<0.05）；在移植患者中，皮质类固醇剂量与 MPAG 的 AUC 呈负相关（P<0.03），体重与健康志愿者和患者中 MPA 的 AUC 呈负相关（P<0.03）。在健康志愿者和患者中，未发现 SLCO1B3 多态性或其他研究变量对 MPA/MPAG 的 AUC（4-12）或 AUC（0-12）有显著影响。
MPA 的 PK 受中国健康个体中 SLCO1B3 多态性的影响。移植患者中 SLCO1B3 多态性无影响可能是由于同时给予环孢素（CsA）。皮质类固醇剂量和体重是 MPA 和 MPAG AUC 的两个重要协变量，在临床应用中应予以考虑。需要进一步进行体内确证研究。
