Brocks D R, Skeith K J, Johnston C, Emamibafrani J, Davis P, Russell A S, Jamali F
Faculty of Pharmacy, University of Alberta, Edmonton, Canada.
J Clin Pharmacol. 1994 Nov;34(11):1088-97. doi: 10.1002/j.1552-4604.1994.tb01986.x.
Hydroxychloroquine (HCQ) is a racemic antiarthritic agent that has a long half-life (t1/2) in plasma and accumulates in blood cells. To study the relationships between HCQ concentrations in plasma, serum, and whole blood and to determine the optimal blood fraction to use for therapeutic drug monitoring of the drug, we studied the relative distribution of the HCQ enantiomers in various fractions of human blood under in vivo and in vitro conditions. Substantially greater concentrations of both enantiomers were found in serum as compared with plasma because of release via platelet activation. After in vitro incubations of the separated blood cells with HCQ, high concentrations of both enantiomers were found in leukocytes, and low concentrations in erythrocytes and platelets; the R:S ratio in vitro was near unity in all of the cells examined. Unlike the in vitro cellular uptake, the concentrations of HCQ in vivo were significantly lower and stereoselective (R:S ratio = 2). There was almost no drug in the polymorphonuclear cells (PMN) in vivo, despite a substantial uptake in vitro after incubation of separated cells. The enantiomeric (R:S) ratio in the urinary excretion of the enantiomers was significantly correlated with that in plasma. The plasma-protein binding of the enantiomers was stereoselective and complimented the cellular uptake findings; the unbound fraction was dependent on the plasma concentrations of alpha 1-acid glycoprotein, but not albumin. Although concentrations in whole blood correlated well with those in lymphocytes and monocytes (the proposed site of HCQ action), stronger correlations were found between concentrations in serum and in the mononuclear cells.
羟氯喹（HCQ）是一种消旋抗关节炎药物，其在血浆中的半衰期较长（t1/2），并在血细胞中蓄积。为了研究血浆、血清和全血中HCQ浓度之间的关系，并确定用于该药物治疗药物监测的最佳血液组分，我们研究了在体内和体外条件下HCQ对映体在人血各组分中的相对分布。由于通过血小板活化释放，血清中两种对映体的浓度均显著高于血浆。将分离的血细胞与HCQ进行体外孵育后，白细胞中发现两种对映体的浓度较高，而红细胞和血小板中的浓度较低；在所检测的所有细胞中，体外的R:S比值接近1。与体外细胞摄取不同，体内HCQ的浓度显著较低且具有立体选择性（R:S比值 = 2）。尽管分离的细胞在体外孵育后有大量摄取，但体内多形核细胞（PMN）中几乎没有药物。对映体尿排泄中的对映体（R:S）比值与血浆中的显著相关。对映体的血浆蛋白结合具有立体选择性，与细胞摄取结果相符；未结合部分取决于α1-酸性糖蛋白的血浆浓度，而不取决于白蛋白。虽然全血中的浓度与淋巴细胞和单核细胞（HCQ作用的假定部位）中的浓度相关性良好，但血清和单核细胞中的浓度之间的相关性更强。
