title: Influence of NAT2 polymorphisms on sulfamethoxazole pharmacokinetics in renal transplant recipients.
abstract: 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 5/ 6, - 6/ 6, - 6/ 7, and - 7/ 7) was significantly greater than that for 56 recipients with the NAT2 rapid acetylator genotype (homozygous for NAT2 4) (766.4 ± 432.3 versus 537.2 ± 257.5 μg-h/ml, respectively; P = 0.0430), whereas there were no significant differences in the SMX AUC(0-24) between the CYP2C9 1/ 1 and - 1/ 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.
authors: Department of Pharmacy, Akita University Hospital, Akita, Japan.
authors: Hideaki
authors: H
authors: Kagaya
authors: Masatomo
authors: M
authors: Miura
authors: Takenori
authors: T
authors: Niioka
authors: Mitsuru
authors: M
authors: Saito
authors: Kazuyuki
authors: K
authors: Numakura
authors: Tomonori
authors: T
authors: Habuchi
authors: Shigeru
authors: S
authors: Satoh
mesh_terms: D000107:Acetylation; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011020:Pneumonia, Pneumocystis / Q000517:prevention & control*; D011110:Polymorphism, Genetic / Q000235:genetics*; D013420:Sulfamethoxazole / Q000493:pharmacokinetics*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics
chemical_list: D015662:Trimethoprim, Sulfamethoxazole Drug Combination; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D013420:Sulfamethoxazole