Szumlanski C L, Weinshilboum R M
Department of Pharmacology, Mayo Medical School/Mayo Clinic/Mayo Foundation, Rochester, MN 55905, USA.
Br J Clin Pharmacol. 1995 Apr;39(4):456-9. doi: 10.1111/j.1365-2125.1995.tb04478.x.
Thiopurine drugs are used in the treatment of inflammatory bowel disease--as are sulphasalazine and its metabolite 5-aminosalicylic acid (ASA). S-Methylation catalyzed by thiopurine methyltransferase (TPMT) is a major pathway in the metabolism of thiopurines. The hypothesis was tested that TPMT might be inhibited by sulphasalazine or isomers of ASA. Sulphasalazine as well as 3-, 4- and 5-ASA inhibited recombinant human TPMT, with IC50 values of 78, 99, 2600 and 1240 microM, respectively. Kinetic studies demonstrated that the inhibition of TPMT by sulphasalazine and ASA isomers was non-competitive with regard to the thiopurine substrate, 6-MP, and was uncompetitive with regard to the methyl donor for the reaction, S-adenosyl-L-methionine. Our observations raise the possibility of a clinically significant drug-drug interaction in patients treated simultaneously with sulphasalazine and thiopurine drugs.
硫嘌呤类药物用于治疗炎症性肠病，柳氮磺胺吡啶及其代谢产物5-氨基水杨酸（ASA）也是如此。硫嘌呤甲基转移酶（TPMT）催化的S-甲基化是硫嘌呤代谢的主要途径。有人提出一个假设，即柳氮磺胺吡啶或ASA的异构体可能会抑制TPMT。柳氮磺胺吡啶以及3-、4-和5-ASA均能抑制重组人TPMT，其IC50值分别为78、99、2600和1240微摩尔。动力学研究表明，柳氮磺胺吡啶和ASA异构体对TPMT的抑制作用，相对于硫嘌呤底物6-巯基嘌呤（6-MP）而言是非竞争性的，而相对于反应的甲基供体S-腺苷-L-甲硫氨酸而言是反竞争性的。我们的观察结果提示，同时接受柳氮磺胺吡啶和硫嘌呤类药物治疗的患者可能存在具有临床意义的药物相互作用。
