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 g-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.

PharmGKB summary

“…Recent studies have shown an association between NAT2 genotypes and sulfamethoxazole pharmacokinetics (PK). In renal transplant patients treated with an immunosuppressive regimen, significantly higher sulfamethoxazole concentrations in slow acetylators (defined as homozygotes or compound heterozygotes for NAT2*5 , *6 , or *7 variants) are seen compared to rapid acetylators (homozygous NAT2*4/*4 ), though the clinical relevance of this is not clear as toxic side effects in this study were not observed [103]. …”

“…Please note; associations in this table are those reported for the individual SNPs rather than studies that grouped SNPs and compared slow and rapid acetylators. a Information regarding variant positions, rsIDs, alleles and phenotypes are from the Consensus Human Arylamine N -Acetyltransferase Gene Nomenclature website http://nat.mbg.duth.gr/ (accessed May 2013). b All positions given use NAT2 reference sequences: NM_000015.2:c, NP_000006.2:p, and NC_000008.10, unless otherwise stated. c Some SNP position information was also added from dbSNP: http://www.ncbi.nlm.nih.gov/projects/SNP/ d Studies often genotype for several variants, and if these are not seen an individual is said to have the * 4 allele, for example in [31, 103]. Therefore the NAT2*4 group may include more rare variants that have not been sequenced/ covered.…”

“… d Studies often genotype for several variants, and if these are not seen an individual is said to have the * 4 allele, for example in [31, 103]. Therefore the NAT2*4 group may include more rare variants that have not been sequenced/ covered.…”

Cotrimoxazole - optimal dosing in the critically ill

“…Patients without the native NAT2*4 allele do not clear SMX as rapidly resulting in accumulation of drug and increased exposure [22]. However, the published research methodology does not describe the ability to differentiate active unaltered SMX from the various metabolites.…”

Role of the Genetic Factors, Detoxication Systems and Oxidative Stress in the Pathogenesis of Endometriosis and Infertility (Review)

“…Наиболее широко в литературе представлены данные исследований, посвященных изучению роли полимор-физма ацетилирования при развитии онкологических заболеваний легких и кишечника [38,39], ревматоидном артрите [40], а также при анализе фармакокинетики и ге-патотоксичности различных препаратов [41,42].…”