Clinical Pharmacokinetics of Artemether and Lumefantrine (Riamet®)
Clinical Pharmacokinetics of Artemether and Lumefantrine (Riamet®)
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蒿甲醚和苯芴醇 (Riamet®) 的临床药代动力学
DOI：
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发表时间：
1999
期刊：
影响因子：
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通讯作者：
M. Thomsen
中科院分区：
文献类型：
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作者：
G. Lefèvre;M. Thomsen
本文报道了蒿甲醚和鲁米芬在健康志愿者和疟疾患者中的临床药代动力学。这两种药物是用于治疗恶性疟疾的固定剂量口服复方蒿甲醚(Riamet®)的有效成分。蒿甲醚吸收速度快，随后从血浆中迅速清除[末端消除半衰期(T1/2β)2至3小时]。其主要代谢物双氢青蒿素(DHA)形成迅速，具有与蒿甲醚相似的清除模式。鲁米芬被缓慢吸收(2小时滞后时间)，然后缓慢从血浆中清除(T1/2β长达10天)。食物摄入显著增加蒿甲醚(>；2倍)和鲁米芬(约16倍)的生物利用度。蒿甲醚和鲁米芬三醇主要由细胞色素P450 3A4(细胞色素P4503A4)同工酶代谢。在健康志愿者和患者中，蒿甲醚、DHA和鲁米芬三种药物的受试者间变异性都很高。抗疟疾药物甲氟喹等CYP3A4底物/抑制剂可以与蒿甲醚联合使用，而不存在临床相关的药物-药物相互作用风险。同样，在与奎宁(一种细胞色素P3A4底物)密切的时间关系共同给药后，用联合蒿甲醚治疗恶性疟原虫不太可能产生重大的医疗危险。蒿甲醚和鲁米芬净的广泛治疗指数和联合蒿甲醚的短期给药表明，药物积累引起的耐受性问题的风险微乎其微。
This paper reports the clinical pharmacokinetics of artemether and lumefantrine in healthy volunteers and in malaria patients. These two drugs are the active components of the fixed-dose oral combination tablet co-artemether (Riamet®), used for the treatment of Plasmodium falciparum malaria.Artemether has a fast absorption rate followed by rapid clearance from plasma [terminal elimination half-life (t1/2β) 2 to 3 hours]. Its major metabolite dihydroartemisinin (DHA) is formed rapidly and has a similar clearance pattern to artemether. Lumefantrine is slowly absorbed (2 hours lag time) followed by a slow clearance from plasma (t1/2β up to 10 days). Food intake significantly increases the bioavailability of both artemether (>2-fold) and lumefantrine (approximately 16-fold).Artemether and lumefantrine are predominantly metabolised by the cytochrome P450 3A4 (CYP3A4) isoenzyme. The intersubject variability for artemether, DHA and lumefantrine is high in both healthy volunteers and patients.CYP3A4 substrates/inhibitors such as the antimalarial mefloquine can be coadministered with co-artemether without clinically relevant risk of drug-drug interaction. Similarly, potential for a significant medical hazard in the management of P. falciparum malaria with co-artemether following co-administration in close temporal relationship with quinine (a CYP3A4 substrate) is unlikely. The wide therapeutic index of artemether and lumefantrine and the short duration of administration of co-artemether suggest that the risk for any tolerability problems from drug accumulation is minimal.