摘要
目的：探讨类粘蛋白（ｏｒｏｓｏｍｕｃｏｉｄ，ＯＲＭ）表型对弱碱性药物奎尼丁血清游离浓度和蛋白结合率的影响。方法：对健康受试者的去唾液酸血清ＯＲＭ用等电聚焦电泳、免疫印迹法进行表型分型。ＯＲＭ１的３种表型分别为纯合子ＯＲＭ１Ｆ１（ｎ＝１０）， ＯＲＭ１Ｓ（ｎ＝８），和杂合子ＯＲＭ１ Ｆ１Ｓ（ｎ＝１０）。受试者口服单剂量的硫酸奎尼丁片２００ｍｇ，测定服药后不同时间血清奎尼丁总浓度（ＲＰ－ＨＰＬＣ）和游离浓度（微超滤离心／ＲＰ－ＨＰＬＣ）。结果：给药后２４ｈ内，３组不同ＯＲＭ１表型者奎尼丁血清总浓度的经时过程、血浆 ｔ１／２、 Ｃｍａｘ和ｔｍａｘ值相似。但ＯＲＭＩ Ｆ１表型组的奎尼丁游离浓度高于ＯＲＭ１Ｓ和ＯＲＭ１ Ｆ１Ｓ表型组，而其蛋自结合率（８０．２１±６．１３Ｔ）却明显低于ＯＲＭ１Ｓ（８９．３１±４．８３％）（Ｐ＜０．０１）和ＯＲＭ１ Ｆ１Ｓ（８７．２６±３．４２％）（Ｐ＜０．０１）表型者；奎尼丁游离药物分数则分别为 ＯＲＭ１ Ｆ１：１９．７９％，ＯＲＭ１ Ｓ １０．６９％和ＯＲＭ１ Ｆ１Ｓ １２．７４％（Ｐ＜０．０１）。结论：不同ＯＲＭ１表型明显影响弱碱性药物奎尼丁的血清游离药物浓度和蛋白结合率； ＯＲＭ１ Ｆ１表?
OBJECTIVE: The orosomucoid(ORM) is a major binding protein in plasma for various basic drugs. METHODS: ORM is coded by two loci closely linked on chromosome. ORM1 locus is high polymorphic and the ORM2 locus is monomorphic in all population. 28 healthy volunteers were selected with three OAN1 phenotypes, containing homozygotes ORM1 F1(n=10) and ORMI S(n=8), and heterozygote ORMI F1S(n=10), identified by isoelectric focusing on polyacrylamide gels following by immunoblotting after desialylation of sera. After a single oral dose of quinidine 200 mg, serum total concentration(HPLC) and unbound concentrations in ultrafiltrate (ultrafiltration/HPLC) were determined, and the pharmacokinetic parameters and protein binding rate were calculated. Serum levels of ORM(553.8-573.2 mg.L-1) and albumin proteins (57.5-58.4 g.L-1) were similar in the three groups(P>0.05). Unbound quinidine concentration in ORM1 F1 phenotype subjects was higher than that in ORMI S and ORMI FIS phenotype; the free drug percentage for the subjects with ORMI F1 phenotype(19.79%) RESULT: 24 hours after dosing was twice times as high as that with ORMI S phenotype(10.96%) (P<0.01). The elimination t1/2 values and the other pharmacokinetics parameters of quinidine were not affected by the different ORM1 phenotypes. These findings suggested that the different ORM1 phenotypes may affect the disposition of quinidine. The functional heterogeneity of ORM1 could be responsible for the differences in plasma binding of quinidine. CONCLUSION: Therefore, monitoring of the unbound quinidine concentration would be important for the patients with different ORM1 phenotypes when quinidine treatment.
出处
《中国临床药理学杂志》
CAS
CSCD
北大核心
2001年第1期59-63,共5页
The Chinese Journal of Clinical Pharmacology
基金
国家自然科学基金!(No 39670843)
国家人事部科研基金!(No 1997-201)
