Influence of NAT2 Polymorphisms on Sulfamethoxazole Pharmacokinetics in Renal Transplant Recipients
Influence of NAT2 Polymorphisms on Sulfamethoxazole Pharmacokinetics in Renal Transplant Recipients
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DOI：
10.1128/aac.05037-11
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发表时间：
2012-02-01
影响因子：
4.9
通讯作者：
Satoh, Shigeru
中科院分区：
文献类型：
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作者：
Kagaya, Hideaki;Miura, Masatomo;Satoh, Shigeru
磺胺甲恶唑(SMX)-甲氧苄啶联合用药在肾移植后的前3至6个月常规用于预防肺囊虫性肺炎。本研究的目的是研究n -乙酰转移酶2 （NAT2）和CYP2C9多态性对118例肾移植受者SMX药代动力学的影响。从肾移植术后第14天开始，患者给予smx -甲氧苄啶400 mg/d -80 mg/d口服，每日1次。在SMX治疗开始后第14天，用高效液相色谱法测定血浆SMX浓度。15例NAT2慢乙酰化基因型(NAT2(star)5/(star)6、-(star)6/(star)6、-(star)6/(star)6、-(star)6/(star)7、-(star)7/(star)7)受体的浓度-时间曲线下的SMX面积（AUC(0-24)）显著大于56例NAT2快速乙酰化基因型（NAT2(star) 4纯合子）受体（766.4 +/- 432.3 vs 537.2 +/- 257.5 mu g-h/ml）；P = 0.0430)，而CYP2C9(star)1/(star)1和-(star)1/(star)3组间SMX AUC（0-24）无显著差异。在多元回归分析中，SMX AUC（0-24）与NAT2慢乙酰化产物多态性（P = 0.0095）和肌酐清除率（P = 0.0499）相关。在SMX给药后6个月内，未观察到NAT2慢乙酰化受体患者肝功能障碍。血浆SMX浓度受NAT2多态性和肾功能的影响。虽然对NAT2慢乙酰化多态性患者的标准SMX用药应同时监测副作用和抑制CYP2C9引起的药物相互作用，但作为预防的低剂量（400mg） SMX用药可能无法提供达到副作用表达所需的药物浓度。更大样本量的进一步研究应该能够阐明SMX血浆浓度与副作用之间的关系。
The sulfamethoxazole (SMX)-trimethoprim drug combination is routinely used as prophylaxis against Pneumocystis pneumonia during the first 3 to 6 months after renal transplantation. The objective of this study was to examine the impact of N-acetyltransferase 2 (NAT2) and CYP2C9 polymorphisms on the pharmacokinetics of SMX in 118 renal transplant recipients. Starting on day 14 after renal transplantation, patients were administered 400 mg/day-80 mg/day of SMX-trimethoprim orally once daily. On day 14 after the beginning of SMX therapy, plasma SMX concentrations were determined by a high-performance liquid chromatography method. The SMX area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for 15 recipients with the NAT2 slow acetylator genotype (NAT2(star)5/(star)6, -(star)6/(star)6, -(star)6/(star)7, and -(star)7/(star)7) was significantly greater than that for 56 recipients with the NAT2 rapid acetylator genotype (homozygous for NAT2(star)4) (766.4 +/- 432.3 versus 537.2 +/- 257.5 mu g-h/ml, respectively; P = 0.0430), whereas there were no significant differences in the SMX AUC(0-24) between the CYP2C9(star)1/(star)1 and -(star)1/(star)3 groups. In a multiple regression analysis, the SMX AUC(0-24) was associated with NAT2 slow acetylator polymorphisms (P = 0.0095) and with creatinine clearance (P = 0.0499). Hepatic dysfunction in NAT2 slow acetylator recipient patients during the 6-month period after SMX administration was not observed. SMX plasma concentrations were affected by NAT2 polymorphisms and renal dysfunction. Although standard SMX administration to patients with NAT2 slow acetylator polymorphisms should be accompanied by monitoring for side effects and drug interaction effects from the inhibition of CYP2C9, SMX administration at a low dose (400 mg) as prophylaxis may not provide drug concentrations that reach the level necessary for the expression of side effects. Further studies with a larger sample size should be able to clarify the relationship between SMX plasma concentration and side effects.