Kuhn U D, Anschütz M, Schmücker K, Schug B S, Hippius M, Blume H H
Institute for Pharmacology and Toxicology, Division of Clinical Pharmacology, Medical Faculty Friedrich Schiller University Jena, Dornburger Strasse 159, 07740 Jena, Germany.
Int J Clin Pharmacol Ther. 2010 Jan;48(1):1-10. doi: 10.5414/cpp48001.
N-acetyltransferase 2 (NAT2) genotype-phenotype relation with sulfasalazine as probe drug by means of detailed genotype analysis and kinetic data evaluation.
Though phenotype analysis of sulfasalazine metabolism has been described before, genotype investigations in this regard are scarce. The influence of different single point mutations on the metabolism of the sulfasalazine metabolite sulfapyridine (SP) should give more insight into the functionality of different alleles especially with those still under discussion.
In two bioavailability studies performed under comparable conditions with 24 healthy subjects of both genders equally distributed, plasma levels of SP and acetylsulfapyridine (Ac-SP) were determined after oral intake of enteric coated formulations of sulfasalazine (500 mg and 1,000 mg, respectively). The resulting metabolic ratios were calculated. NAT2 genotype was analyzed in parallel for all subjects deducing haplotype set as well as putative functional phenotype as (homozygous or heterozygous) rapid acetylator (RA) or slow acetylator (SA) and correlated with the PK results.
RA genotype in the overall study population was seen with 45.5% (including 6.8% homozygous wildtype *4/*4) and SA genotype with 54.5%. Compared to RA genotype, apparent terminal elimination half-life of SP as well as of Ac-SP was prolonged in the SA genotype population, C(max) and AUC values of SP were higher whereas average C(max) value of Ac-SP was lower (with AUC only some tendency to lower values). In general, phenotype-genotype correlation was good with only few exceptions. Strongest functional effect on enzyme activity was noticed in slow acetylators carrying the 341T > C mutation, followed by 590G > A mutation whereas the influence of 857G > A was considerably less pronounced. Homozygous 803A > G mutation (lysine > arginine shift) did not reveal enzyme activity reduction.
通过详细的基因型分析和动力学数据评估，研究N - 乙酰转移酶2（NAT2）基因型与以柳氮磺胺吡啶为探针药物的表型关系。
虽然之前已经描述过柳氮磺胺吡啶代谢的表型分析，但这方面的基因型研究却很少。不同单点突变对柳氮磺胺吡啶代谢物磺胺吡啶（SP）代谢的影响，应该能更深入地了解不同等位基因的功能，尤其是那些仍在讨论中的等位基因。
在两项条件相当的生物利用度研究中，对24名健康受试者（男女各半）口服柳氮磺胺吡啶肠溶制剂（分别为500毫克和1000毫克）后的血浆SP和乙酰磺胺吡啶（Ac - SP）水平进行了测定。计算得出代谢率。同时对所有受试者进行NAT2基因型分析，推断单倍型组合以及推定的功能表型，即（纯合或杂合）快速乙酰化者（RA）或慢速乙酰化者（SA），并将其与药代动力学结果相关联。
在整个研究人群中，RA基因型占45.5%（包括6.8%的纯合野生型*4/*4），SA基因型占54.5%。与RA基因型相比，SA基因型人群中SP以及Ac - SP的表观终末消除半衰期延长，SP的C(max)和AUC值更高，而Ac - SP的平均C(max)值更低（AUC仅略有降低趋势）。总体而言，表型 - 基因型相关性良好，仅有少数例外。在携带341T > C突变的慢速乙酰化者中，对酶活性的功能影响最强，其次是590G > A突变，而857G > A的影响则明显较小。纯合803A > G突变（赖氨酸>精氨酸移位）未显示酶活性降低。
