How much fat is necessary to optimize lumefantrine oral bioavailability?
How much fat is necessary to optimize lumefantrine oral bioavailability?
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DOI：
10.1111/j.1365-3156.2006.01784.x
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发表时间：
2007-02-01
影响因子：
3.3
通讯作者：
Nosten, Francois
中科院分区：
文献类型：
--
作者：
Ashley, Elizabeth A.;Stepniewska, Kasia;Nosten, Francois
背景 蒿甲醚-本芴醇（AL）是唯一在国际上注册并大规模使用的固定的、以青蒿素为基础的复方抗疟药。疏水性亲脂性苯芴醇成分的吸收在个体之间存在很大差异，并且通过脂肪共同给药而大大增加；但急性疟疾患者经常出现恶心和厌食的症状，因此很难遵守饮食建议。本研究的目的是描述脂肪联合给药与本芴醇相对生物利用度之间的剂量-反应关系，以确定优化吸收所需的最小脂肪量。 方法 我们在 12 名健康志愿者中进行了多重交叉药代动力学研究。这比较了空腹状态下单剂量 AL 与 0、10、40、150 和 500 ml 豆浆（相当于 0、0.32、1.28、4.8 和 16 g 脂肪）给药后本药的血浆浓度-时间曲线下面积（AUC）。所有受试者的所有牛奶补充剂量均经过 3 至 4 周的洗脱期测试。 结果 豆浆服用量与本芴醇生物利用度之间存在剂量-反应关系。 AL 与豆浆一起给药可使本芴醇 AUC 增加五倍以上。获得 90% 最大效果（以本芴醇 AUC 计）所需的人群平均估计豆奶量为 36 ml（相当于 1.2 g 脂肪）。 结论 需要将蒿甲醚-本芴醇与相对少量的脂肪（如豆浆）共同给药，以确保健康成年志愿者对本芴醇的最大吸收。
Background Artemether-lumefantrine (AL) is the only fixed, artemisinin-based combination antimalarial drug which is registered internationally and deployed on a large scale. Absorption of the hydrophobic lipophilic lumefantrine component varies widely between individuals and is greatly increased by fat coadministration; but patients with acute malaria are frequently nauseated and anorexic, making dietary advice difficult to comply with. The aim of this study was to describe the dose-response relationship between coadministration of fat and relative lumefantrine bioavailability, in order to determine the minimum amount of fat necessary to optimize absorption.Method We conducted a multiple crossover pharmacokinetic study in 12 healthy volunteers. This compared the area under the plasma concentration-time curve (AUC) for lumefantrine after administration of a single dose of AL in the fasting state given with 0, 10, 40, 150 and 500 ml of soya milk corresponding to 0, 0.32, 1.28, 4.8 and 16 g of fat. All volumes of milk supplements were tested in all subjects with a 3- to 4-week washout period in-between.Results A dose-response relationship was demonstrated between the volume of soya milk administered and lumefantrine bioavailability. AL administration with soya milk increased the lumefantrine AUC more than five fold. The population mean estimated volume of soya milk required to obtain 90% of maximum effect (in terms of lumefantrine AUC) was 36 ml (corresponding to 1.2 g of fat).Conclusion Coadministration of artemether-lumefantrine with a relatively small amount of fat (as soya milk) was required to ensure maximum absorption of lumefantrine in healthy adult volunteers.