Wein Sharon, Taudon Nicolas, Maynadier Marjorie, Tran Van Ba Christophe, Margout Delphine, Bordat Yann, Fraisse Laurent, Wengelnik Kai, Cerdan Rachel, Bressolle-Gomeni Françoise, Vial Henri J
Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université de Montpellier, Montpellier, France
Pharmacocinétique Clinique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France.
Antimicrob Agents Chemother. 2017 Jul 25;61(8). doi: 10.1128/AAC.00352-17. Print 2017 Aug.
Albitiazolium is the lead compound of bisthiazolium choline analogues and exerts powerful and antimalarial activities. Here we provide new insight into the fate of albitiazolium in mice and how it exerts its pharmacological activity. We show that the drug exhibits rapid and potent activity and has very favorable pharmacokinetic and pharmacodynamic properties. Pharmacokinetic studies in -infected mice indicated that albitiazolium rapidly and specifically accumulates to a great extent (cellular accumulation ratio, >150) in infected erythrocytes. Unexpectedly, plasma concentrations and the area under concentration-time curves increased by 15% and 69% when mice were infected at 0.9% and 8.9% parasitemia, respectively. Albitiazolium that had accumulated in infected erythrocytes and in the spleen was released into the plasma, where it was then available for another round of pharmacological activity. This recycling of the accumulated drug, after the rupture of the infected erythrocytes, likely extends its pharmacological effect. We also established a new viability assay in the -infected mouse model to discriminate between fast- and slow-acting antimalarials. We found that albitiazolium impaired parasite viability in less than 6 and 3 h at the ring and late stages, respectively, while parasite morphology was affected more belatedly. This highlights that viability and morphology are two parameters that can be differentially affected by a drug treatment, an element that should be taken into account when screening new antimalarial drugs.
阿比特唑lium是双噻唑lium胆碱类似物的先导化合物，具有强大的抗疟活性。在此，我们对阿比特唑lium在小鼠体内的命运及其发挥药理活性的方式提供了新的见解。我们表明，该药物具有快速且强效的活性，并且具有非常良好的药代动力学和药效学特性。在感染疟原虫的小鼠中进行的药代动力学研究表明，阿比特唑lium在感染的红细胞中迅速且特异性地大量积累（细胞积累率>150）。出乎意料的是，当小鼠分别以0.9%和8.9%的疟原虫血症感染时，血浆浓度和浓度-时间曲线下面积分别增加了15%和69%。在感染的红细胞和脾脏中积累的阿比特唑lium释放到血浆中，然后可用于新一轮的药理活性。感染的红细胞破裂后，积累药物的这种循环利用可能会延长其药理作用。我们还在感染疟原虫的小鼠模型中建立了一种新的活力测定法，以区分速效和慢效抗疟药。我们发现，阿比特唑lium在环状期和晚期分别在不到6小时和3小时内损害了疟原虫的活力，而疟原虫形态受到的影响则更晚。这突出表明，活力和形态是两个可能受到药物治疗不同影响的参数，这是筛选新抗疟药物时应考虑的一个因素。
