Yokogawa K, Nakaharu T, Ishizaki J, Ozaki E, Takeda Y, Mabuchi H, Matsushita R, Kimura K, Nakashima E, Ichimura F, Miyamoto K
Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1, Takara-machi, 920-8641, Kanazawa, Japan.
Int J Pharm. 2001 Oct 23;229(1-2):183-91. doi: 10.1016/s0378-5173(01)00864-x.
We found that N-acetylation polymorphism can be evaluated from the disposition kinetics of sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA) and their acetylated metabolites generated by N-acetyltransferase (NAT2) after oral administration of salicylazosulfapyridine (SASP). In 126 Japanese subjects, the homozygote of NAT24 was the most frequent (40%), followed by heterozygotes of NAT24 and mutant genes (28% NAT24/6A, 15% NAT24/7B, and 2% NAT24/5B). Combinations of mutant genes accounted for 16%. When the relationship between the molar ratio of N-acetyl-SP (Ac-SP)/SP or N-acetyl-5-ASA(Ac-5-ASA)/5-ASA in serum and five genotypes of polymorphic NAT2 was examined in patients who received multiple doses of SASP, the molar ratios of Ac-SP/SP, rather than Ac-5-ASA/5-ASA tended to decrease according to the classification of genotype. We calculated the pharmacokinetic parameters in healthy subjects with various genotypes of polymorphic NAT2 after a single p.o. administration of SASP, according to a model of the SP metabolic pathways. The molar ratios of Ac-SP/SP in serum and urine were simulated using these parameters, and the molar ratio of Ac-SP/SP in urine at 4 days after the first administration could be categorized into ranges that were specific to various NAT2* genotypes. Thus, we were able to predict the N-acetylation polymorphic genotypes of patients by measuring the molar ratio of Ac-SP/SP in urine, after administration of SASP.
我们发现，口服柳氮磺胺吡啶（SASP）后，可根据磺胺吡啶（SP）和5-氨基水杨酸（5-ASA）及其由N-乙酰转移酶（NAT2）生成的乙酰化代谢产物的处置动力学来评估N-乙酰化多态性。在126名日本受试者中，NAT24纯合子最为常见（40%），其次是NAT24与突变基因的杂合子（NAT24/6A为28%，NAT24/7B为15%，NAT24/5B为2%）。突变基因组合占16%。在接受多剂量SASP的患者中，检测血清中N-乙酰-SP（Ac-SP）/SP或N-乙酰-5-ASA（Ac-5-ASA）/5-ASA的摩尔比与多态性NAT2的五种基因型之间的关系时，Ac-SP/SP的摩尔比而非Ac-5-ASA/5-ASA的摩尔比往往会根据基因型分类而降低。根据SP代谢途径模型，我们计算了单次口服SASP后具有多态性NAT2不同基因型的健康受试者的药代动力学参数。使用这些参数模拟血清和尿液中Ac-SP/SP的摩尔比，首次给药后4天尿液中Ac-SP/SP的摩尔比可分为特定于各种NAT2*基因型的范围。因此，我们能够通过在给予SASP后测量尿液中Ac-SP/SP的摩尔比来预测患者的N-乙酰化多态性基因型。
