Rozman Blaz
Department of Rheumatology, Medical Centre Ljubljana, Ljubljana, Slovenia.
Clin Pharmacokinet. 2002;41(6):421-30. doi: 10.2165/00003088-200241060-00003.
Leflunomide is the first disease-modifying antirheumatic drug to be approved for rheumatoid arthritis in the past 10 years. Orally administered leflunomide is almost completely converted into its active metabolite A77 1726 (hereafter referred to as M1). M1 displays linear pharmacokinetics at the dosages of leflunomide used in clinical practice. It has a long elimination half-life (approximately 2 weeks), reaching a steady state after approximately 20 weeks. M1 is highly bound to plasma proteins. The pharmacokinetics of M1 are not affected by food intake, and dosage requirements are not influenced by age or gender. Approximately 90% of a single dose of leflunomide is eliminated, 43% in urine, primarily as leflunomide glucuronides and an oxalinic acid derivative of M1, and 48% in faeces, primarily as M1. Elimination can be dramatically increased by using charcoal or cholestyramine. In vitro studies have shown no major influence of leflunomide on the metabolism of analgesics, nonsteroidal anti-inflammatory drugs and methotrexate, drugs usually used in the treatment of rheumatoid arthritis. In clinical studies with a limited number of patients using these drugs concomitantly, no safety problems appeared. Nonspecific inducers of cytochrome P450 (CYP) and some drugs metabolised by CYP2C9 affect the metabolism of M1, and caution should be used in patients cotreated with them. Additional in vitro and in vivo pharmacokinetic studies are needed to better understand the nonenzymatic and enzymatic metabolism of leflunomide. Additional clinical trials should be performed in order to find new indications for leflunomide in other autoimmune diseases, and new combination therapeutic strategies in rheumatoid arthritis. This review is a summary of current knowledge of the pharmacokinetics of leflunomide, focusing primarily on humans and in particular on patients with rheumatoid arthritis.
来氟米特是过去10年中首个被批准用于类风湿关节炎的改善病情抗风湿药。口服来氟米特几乎完全转化为其活性代谢产物A77 1726（以下简称M1）。M1在临床实践中使用的来氟米特剂量下呈现线性药代动力学。它的消除半衰期很长（约2周），约20周后达到稳态。M1与血浆蛋白高度结合。M1的药代动力学不受食物摄入影响，剂量需求也不受年龄或性别的影响。单次服用的来氟米特约90%被消除，43%经尿液排出，主要是来氟米特葡糖醛酸化物和M1的草氨酸衍生物，48%经粪便排出，主要是M1。使用活性炭或考来烯胺可显著增加消除。体外研究表明，来氟米特对通常用于治疗类风湿关节炎的镇痛药、非甾体抗炎药和甲氨蝶呤的代谢没有重大影响。在少数同时使用这些药物的患者的临床研究中，未出现安全问题。细胞色素P450（CYP）的非特异性诱导剂和一些由CYP2C9代谢的药物会影响M1的代谢，与这些药物联合治疗的患者应谨慎使用。需要进行更多的体外和体内药代动力学研究，以更好地了解来氟米特的非酶和酶代谢。应进行更多的临床试验，以便在其他自身免疫性疾病中找到来氟米特的新适应症，以及在类风湿关节炎中找到新的联合治疗策略。本综述总结了来氟米特药代动力学的当前知识，主要关注人类，特别是类风湿关节炎患者。
