Orosomucoid (α1-acid glycoprotein) plasma concentration and genetic variants:: Effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation
Orosomucoid (α1-acid glycoprotein) plasma concentration and genetic variants:: Effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation
复制标题
DOI：
10.1016/j.clpt.2006.06.006
复制
发表时间：
2006-10-01
影响因子：
6.7
通讯作者：
Eap, Chin B.
中科院分区：
文献类型：
--
作者：
Colombo, Sara;Buclin, Thierry;Eap, Chin B.
背景和目的：蛋白水解酶抑制物与α(1)-酸性糖蛋白(orosomucid，ORM)高度结合，ORM是一种由两个多态基因编码的急性期血浆蛋白，可能调节它们的处置。我们的目的是确定ORM浓度和表型对依地那韦、洛比那韦和奈非那韦的表观清除量(CLAPP)和细胞蓄积的影响。将主要与白蛋白结合的依法韦仑作为对照药物。采集了434例人类免疫缺陷病毒感染者的血浆和细胞样本。全血浆。结果：依地那韦浓度(n=36)强烈影响依地那韦的药物浓度(r(2)=0.47[P=.00004])，尤其是在利托那韦存在的情况下(r(2)=0.54[P=0.004])。洛比那韦对药物浓度的影响较小(n=81)(r(2)=0.18[P=0.0001])。对于这两种药物，ORM1 S浓度的变化主要解释了这种影响(r(2)=0.55[P=.00004]和r(2)=0.23[P=.0002])。F1F1个体的Indinavir Clapp显著高于F1个体和SS患者(分别为41·3、23·4和10·3 L/h[P=0·0004]和21·1、13·2和10·1 L/h[P=0·05])。洛比那韦细胞暴露不受ORM丰度和表型的影响。结论：ORM浓度和表型对依地那韦和洛匹那韦的药代动力学有一定的影响，但不影响它们的细胞暴露。在适当解释治疗药物监测结果时，应考虑到ORM的这种混杂影响。对于依地那韦和洛比那韦来说，非结合药物血药浓度的测量是否比总药物浓度提供更有意义的信息，还需要进一步的研究。
Background and Objective: Protease inhibitors are highly bound to orosomucoid (ORM) (alpha(1)-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CLapp) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.Methods. Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma. and cellular drug concentrations and ORM concentrations and phenotypes were determined.Results: Indinavir CLapp was strongly influenced by ORM concentration (n = 36) (r(2) = 0.47 [P = .00004]), particularly in the presence of ritonavir (r(2) = 0.54 [P = .004]). Lopinavir CLapp was weakly influenced by ORM concentration (n = 81) (r(2) = 0 .18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r(2) = 0.55 [P = .00004] and r(2) = 0.23 [P = .0002], respectively). Indinavir CLapp was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics.Conclusion: ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.