类粘蛋白的遗传表型对阿米替林血浆游离型药物浓度和蛋白结合率的影响

The effect of orosomucoid phenotypes on plasma free drug concentration and plasma protein binding of amitriptyline

目的：探讨类粘蛋白(orosomucoid, ORM)表型对弱碱性药物阿米替林血浆游离浓度和蛋白结合率的影响. 方法：对28名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的三种表型分别为纯合子ORM1 F1 (n=10)、ORM1 S (n=8)和杂合子ORM1 F1S(n=10).受试者口服单剂量的硫酸阿米替林片50 mg,测定服药后不同时间血浆阿米替林总浓度(RP-HPLC)和游离浓度(微超滤离心/RP-HPLC). 结果：给药后12和24 h,三组不同ORM1表型者阿米替林血浆总浓度的经时过程、血浆t1/2、Cmax和tmax值相似.与ORM1 S表型组比较,ORM1 F1表型组的阿米替林游离浓度较高；而蛋白结合率较低,12 h为(82.77±4.05)%,24 h为(79.99±4.39)% (P<0.01).杂合子ORM1 F1S表型组的游离药物浓度和蛋白结合率介于两组纯合子表型之间. 结论：不同ORM1表型,将明显影响弱碱性药物阿米替林的血清游离药物浓度和蛋白结合率；ORM1 F1表型者药物的血浆蛋白结合率最低,而游离型药物浓度最高.临床用药中应予以注意,并适当调整给药剂量.

Objectives: To study the effect of the different ORM1 phenotypes on plasma free drug concentration and plasma protein binding of amitriptyline. Methods: Twenty eight healthy volunteers with thre e ORM1 phenotypes containing homozygotes ORM1 F1( n =10) and ORM1 S( n =8), and heteroz ygote ORM1 F1S( n =10) identified by isoelectri c focusing on polyacrylamide gels following by immunoblotting after desialylation of sera were selected. After a single 5 0 mg of amitriptyline hydrochloride per os, plasma total and free(in ultrafiltrate) concentrations were determined and the pharmacokinetic parameters and the binding percentage in sera of the drug were calculated. Results: Plasma levels of OR M and albumin proteins were similar in the three groups( P >0.05). The elimination t 1/2 values and the other pharmacokineti cs parameters of amitriptyline did not be affected by the different ORM1 phenotypes. Free amitriptyline concentration i n ORM1 F1 phenotype subjects was significant higher than that in ORM1 S phe notype( P <0.01), but percentage of the plasma protein binding after dosing for the subjects with ORM1 F1 phenotype, (82. 77±4.05)% at 12 h, (79.99±4.39)% at 24 h was lower than that with ORM1 S phenotype( P <0.01). Conclusions: The different ORM1 phenotypes may affect the dispositi on of amitriptyline in the subjects. T he functional heterogeneity of ORM1 could be responsible for the differences in plasma protein binding of amitriptyline. Therefore, monitoring of the free amitriptyli ne concentration would be important for the patients with different ORM1 phenotypes when amitriptyline treatment.