Tett S E
Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, Australia.
Clin Pharmacokinet. 1993 Nov;25(5):392-407. doi: 10.2165/00003088-199325050-00005.
The pharmacokinetics of the slow acting antirheumatic drugs (SAARDs), hydroxychloroquine, chloroquine, penicillamine, the gold complexes and sulphasalazine, in humans have been studied. For all these drugs, both in controlled clinical trials and in empirical observations from rheumatological practice, delays of several months are reported before full clinical effects are achieved. Variability in response is also characteristic of these agents. Pharmacokinetic factors may partially explain these clinical observations. Delays in the achievement of steady-state concentrations or of concentrations likely to have a therapeutic benefit may occur because of slow drug accumulation. Variable concentrations may arise after standard administered doses because of interindividual pharmacokinetic variability. These factors are likely to contribute to the delay in response and the variable response, respectively. Pharmacokinetics of the antimalarials, hydroxychloroquine and chloroquine, are characterised by extensive tissue sequestration with reported volumes of distribution in the thousands of litres. Both drugs have reported elimination half-lives of greater than 1 month. A 2- to 3-fold range occurs in the fraction of an oral dose absorbed from a tablet formulation. Variable interindividual clearance is also reported. Hydroxychloroquine and chloroquine are administered as racemates. Enantioselective disposition of both compounds occurs, again with notable interindividual variability. Sulphasalazine is split in the large intestine into sulphapyridine, proposed to be the active compound in rheumatoid arthritis, and mesalazine (5-aminosalicylic acid). Sulphapyridine is metabolised partly by acetylation, the rate of which is under genetic control. A wide range of sulphapyridine steady-state concentrations are reported after standard doses of sulphasalazine. The gold complexes are administered either intramuscularly or in an oral form (auranofin). Gold is widely distributed in the body. Very long terminal elimination half-lives and slow accumulation rates are reported. Penicillamine is administered orally. Its bioavailability is variable and may decrease by as much as 70% in the presence of food, antacids and iron salts. Penicillamine forms disulphide bonds with many proteins in the blood and tissues, creating potential slow release reservoirs of the drug. Like the other SAARDs, gold complexes and penicillamine are found in a wide range of blood concentrations after administration in standard doses to different individuals. More research must be conducted into the concentration-effect relationships of the SAARDs before the pharmacokinetic characteristics of these drugs can be used effectively to optimise patient therapy.
人们已经对慢作用抗风湿药（SAARDs），如羟氯喹、氯喹、青霉胺、金制剂和柳氮磺胺吡啶在人体内的药代动力学进行了研究。对于所有这些药物，无论是在对照临床试验还是在风湿病临床实践中的经验观察中，均报告称在获得充分临床疗效之前有几个月的延迟。反应的变异性也是这些药物的特征。药代动力学因素可能部分解释了这些临床观察结果。由于药物蓄积缓慢，可能会出现达到稳态浓度或可能具有治疗益处的浓度延迟的情况。由于个体间药代动力学变异性，标准给药剂量后可能会出现浓度变化。这些因素可能分别导致反应延迟和反应变异性。抗疟药羟氯喹和氯喹的药代动力学特征是广泛的组织潴留，报告的分布容积达数千升。两种药物的消除半衰期均报告超过1个月。片剂剂型口服剂量的吸收分数有2至3倍的范围。个体间清除率也存在差异。羟氯喹和氯喹以消旋体给药。两种化合物均存在对映体选择性处置，个体间差异也很显著。柳氮磺胺吡啶在大肠中分解为磺胺吡啶（被认为是类风湿关节炎中的活性化合物）和美沙拉嗪（5-氨基水杨酸）。磺胺吡啶部分通过乙酰化代谢，其速率受基因控制。标准剂量柳氮磺胺吡啶后报告的磺胺吡啶稳态浓度范围很广。金制剂通过肌肉注射或口服（金诺芬）给药。金在体内广泛分布。报告的终末消除半衰期非常长，蓄积速率缓慢。青霉胺口服给药。其生物利用度可变，在有食物、抗酸剂和铁盐存在时可能会降低多达70%。青霉胺与血液和组织中的许多蛋白质形成二硫键，形成潜在的药物缓释库。与其他SAARDs一样，标准剂量给药给不同个体后，金制剂和青霉胺在血液中的浓度范围很广。在这些药物的药代动力学特征能够有效地用于优化患者治疗之前，必须对SAARDs的浓度-效应关系进行更多研究。
